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Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population. In addition, we discuss the phenotypic overlap between SGBS and Beckwith-Wiedemann Spectrum., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Objective: Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion of acromegaly., Design/patients: PubMed/Medline search was conducted to identify reported pseudoacromegaly cases, which were systematically reviewed to ensure they met eligibility criteria: (1) presentation suggestive of acromegaly; (2) acromegaly excluded based on normal GH, IGF-1 and/or GH suppression on oral glucose tolerance test (OGTT-GH); (3) diagnosis of the pseudoacromegaly condition was established. Data were retrieved from each case and analysed collectively., Results: Of 76 cases, 47 were males, mean ages at presentation and at first acromegaloid symptoms were 28 ± 16 and 17 ± 10 years, respectively. Most common conditions were pachydermoperiostosis (47%) and insulin-mediated pseudoacromegaly (IMP) (24%). Acromegaloid facies (75%) and acral enlargement (80%) were the most common features. Measurement of random GH was reported in 65%, IGF-1 in 79%, OGTT-GH in 51%. GH excess was more frequently excluded based on two tests (53%). Magnetic resonance imaging (MRI) was performed in 30 patients, with pituitary adenoma or hyperplasia being reported in eight and three patients, respectively. Investigations differed between cases managed by endocrine and non-endocrine specialists, the former requesting more often IGF-1, OGTT-GH and pituitary MRI., Conclusions: Pseudoacromegaly is a challenging entity that may be encountered by endocrinologists. Pachydermoperiostosis and IMP are the conditions most often mimicking acromegaly. Adequate assessment of GH/IGF-1 is crucial to exclude acromegaly, which may be better performed by endocrinologists. Pituitary incidentalomas are common and require careful judgement to prevent unnecessary pituitary surgery., (© 2024 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A newborn baby born at 34 weeks and 5 days gestation was admitted for prematurity, dysmorphic features and congenital heart defects. Antenatal scan at 21 weeks showed a large-for-gestational-age foetus with a large abdominal circumference and liver, ventricular septal defect, right prominent renal pelvis and echogenic bowel. Antenatal genetic tests for overgrowth syndromes were negative. The mother had early onset pre-eclampsia. After birth, an overgrowth syndrome was still suspected despite the baby having normal birth parameters. Raw data of the trio whole exome sequencing from the amniocentesis sample were manually inspected. Hemizygous exon 7 deletion in the GPC3 gene was found, and a postnatal diagnosis of Simpson-Golabi-Behmel syndrome, a rare overgrowth syndrome, was made. This case report discusses the significance of antenatal findings, an atypical presentation of a rare syndrome and the obstacles of diagnostic genetic testing., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Glypican-3 (GPC3) is an oncofetal protein involved in cellular signaling, strongly expressed in the placenta, absent or diminished in postnatal life, but often increased in human malignancies. Germline loss-of-function variants of GPC3 gene are associated with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), a rare recessive X-linked overgrowth disease characterized by typical facial features, congenital abnormalities, and an increased risk of developing childhood cancers., Methods: A clinical suspicion of SGBS1 was postulated for a newborn with prenatal history of overgrowth and polyhydramnios, presenting with neonatal weight and length >99th percentile, coarse facies, iris and retinal coloboma, supernumerary nipples, and splenomegaly. While waiting for whole-genome sequencing (WGS) results, we investigated placental GPC3 immunohistochemical expression in the proband, in three additional cases of SGBS1, and disorders commonly associated with fetal macrosomia and/or placentomegaly., Results: WGS in the proband identified a likely pathogenic maternally inherited missense variant in GPC3: c.1645A > G, (p.Ile549Val), and GPC3 immunohistochemistry demonstrated full-thickness loss of stain of the placental parenchyma. The same pattern ("null") was also present in the placentas of three additional cases of SGBS1, but not in those of unaffected controls., Discussion: Immunohistochemical expression of GPC3 in the placenta is highly reproducible. Our findings showed that a "null pattern" of staining is predictive of SGBS1 and represents a valuable aid in the differential diagnosis of fetal macrosomias, allowing targeted genetic testing and earlier diagnosis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pseudoacromegaly encompasses a heterogeneous group of conditions in which patients have clinical features of acromegaly or gigantism, but no excess of GH or IGF-1. Acromegaloid physical features or accelerated growth in a patient may prompt referral to endocrinologists. Because pseudoacromegaly conditions are rare and heterogeneous, often with overlapping clinical features, the underlying diagnosis may be challenging to establish. As many of these have a genetic origin, such as pachydermoperiostosis, Sotos syndrome, Weaver syndrome, or Cantú syndrome, collaboration is key with clinical geneticists in the diagnosis of these patients. Although rare, awareness of these uncommon conditions and their characteristic features will help their timely recognition., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked overgrowth syndrome. The main clinical manifestations are overgrowth and multiple malformations., Case Presentation: A 38-year-old Chinese woman was pregnant with dichorionic-diamniotic (DCDA) twins after in-vitro fertilization. Series of ultrasound examinations indicated that the measurements (abdominal circumference and estimated foetal weight) of one twin were significantly greater than those of the other one. The genetic testing results of the larger baby indicated of Simpson-Golabi-Behmel syndrome., Conclusion: SGBS is difficult to diagnose due to different clinical manifestations. Clinicians need to be more aware of typical SGBS's clinical findings and choose genetic testing methods individually to improve its prenatal diagnosis., (© 2022. The Author(s).)

Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty-one subjects (six females) formed the study group with ages between 3.5 months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K-AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1-related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first-tier genomic test rather than CMA in OGID., (© 2021 Wiley Periodicals LLC.)

Context: Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear., Case Description: A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH., Conclusion: This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction : Acromegaly and gigantism entail increased morbidity and mortality if left untreated, due to the systemic effects of chronic GH and IGF-1 excess. Guidelines for the diagnosis and treatment of patients with GH excess are well established; however, the presentation, clinical behavior and response to treatment greatly vary among patients. Numerous markers of disease behavior are routinely used in medical practice, but additional biomarkers have been recently identified as a result of basic and clinical research studies. Areas covered : This review focuses on genetic, molecular and genomic features of patients with GH excess that have recently been linked to disease progression and response to treatment. A PubMed search was conducted to identify markers of disease behavior in acromegaly and gigantism. Markers already considered as part of routine studies in clinical care guidelines were excluded. Literature search was expanded for each marker identified. Novel markers not included or only partially covered in previously published reviews on the subject were prioritized. Expert opinion : Recognizing the most relevant markers of disease behavior may help the medical team tailoring the strategies for approaching each case of acromegaly and gigantism. This customized plan should make the evaluation, treatment and follow up process more efficient, greatly improving the patients' outcomes.

Introduction: Pituitary gigantism is a rare but significant paediatric condition with complexities surrounding diagnosis and management. Transsphenoidal surgery (TSS) is the treatment of choice; however, medical treatment is often considered as adjuvant therapy., Case: A 10½ -year-old boy presented with tall stature and a height velocity of 11 cm/year. His height was 178.7 cm (+5.8 SD above mean) and insulin-like growth factor-1 (IGF-1) was elevated. An oral glucose tolerance test demonstrated non-suppression of growth hormone (GH). Initial contrast MRI was inconclusive, but C-11 methionine functional positron emission tomography CT identified a 6 mm pituitary microadenoma. A multidisciplinary team clinic held with the family allowed discussion about medical and surgical treatment options. Due to a number of factors including the patient's young age, prepubertal status, a wish to allow him to settle into his new high school and his desire to reach a final height taller than his father's height, it was decided to try medical therapy first with a somatostatin analogue. Pubertal induction was also commenced and bilateral epiphysiodesis surgery performed. Initial response to octreotide was positive; however, 4 months into therapy his IGF-1 was climbing and a repeat GH profile was not fully suppressed. The patient therefore proceeded to have successful TSS excision of the adenoma., Conclusion: Rare cases such as this require sharing of knowledge and expertise, so the best possible care is offered. It is often necessary to work across sites and disciplines. Each case requires an individual approach tailored to the patient and their family., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is caused by mutations in GPC3 or in both GPC3 and GPC4. Physical manifestations of SGBS1 include fetal overgrowth and macrostomia, macroglossia. Subclinical hypothyroidism has never been reported in SGBS1 cases., Patient Concerns: An 8-days-old boy was referred to our hospital with persistent hypoglycemia and special facies. And the infant showed elevated levels of thyroid-stimulating hormone (TSH). Free T4 and free T3 were normal., Diagnoses: Definitive diagnosis of SGBS1 depends on clinical features and genetic testing. A nonsense mutation (c.1515C > A, p. Cys505*) was tested by whole-exome sequencing., Interventions: Normal blood glucose levels were maintained with glucose infusions. Levothyroxine was given to the patient for treating subclinical hypothyroidism., Outcomes: The parents decided to abandon the treatment of the patient. We learned that the patient died of a lung infection by a telephone follow-up., Lessons: Subclinical hypothyroidism could be added to the known clinical manifestations of SGBS1.

Context: X-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs., Case Description: The patient's mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For more than 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During preconception planning, X-LAG was diagnosed: single-nucleotide polymorphism microarray showed chromosome Xq26.3 microduplication. After conception, single-nucleotide polymorphism microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother's pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and pituitary-specific transcription factor-1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and octamer-binding transcription factor 4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index, 5.6% in the mother and 8.5% in the infant, the highest reported in X-LAG., Conclusions: This is a prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential., (Copyright © 2019 Endocrine Society.)

Introduction: Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities., Materials and Methods: Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016., Results: All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma., Conclusions: This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.

Name of the Disease (synonyms): Simpson-Golabi-Behmel syndrome (SGBS). OMIM# OF THE DISEASE: 312870., Name of the Analysed Genes or Dna/chromosome Segments: GPC3. OMIM# OF THE GENE(S): 300037. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the GPC3 gene(s) in ⊠ diagnostic, ☐ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.

We present a case of a Chinese child with X-linked Simpson-Golabi-Behmel syndrome (SGBS). To the best of our knowledge, this is the first report of 46,XY disorders of sex development (ambiguous genitalia, cryptorchidism, and uterus in the pelvis) in surviving SGBS patients. Other external anomalies included characteristic facial anomalies, overgrowth, macrocephaly, organomegaly, pectus excavatum, and cryptorchidism. It could be that the GPC3 gene mutation caused Leydig cell dysfunction in our patient. Disorders of sex development can be included as part of the clinical spectrum of SGBS., (© 2019 Wiley Periodicals, Inc.)

Simpson-Golabi-Behmel syndrome type I (SGBS, OMIM312870), caused by defects of the GPC3 and GPC4 genes on chromosome Xq26, is an X-linked recessive macrosomia/multiple congenital anomaly disorder characterized by somatic overgrowth, coarse facial features, variable congenital anomalies, increased tumor risk, and mild-to-moderate neurodevelopmental anomalies. We report the postmortem findings in 3 second-trimester male siblings with SGBS who displayed ambiguous genitalia (in all 3) and gonadal dysgenesis (ovotestis) (in 1), thus expanding the SGBS spectrum to include these disorders of sex development.

Individuals with acromegaloid physical appearance or tall stature may be referred to endocrinologists to exclude growth hormone (GH) excess. While some of these subjects could be healthy individuals with normal variants of growth or physical traits, others will have acromegaly or pituitary gigantism, which are, in general, straightforward diagnoses upon assessment of the GH/IGF-1 axis. However, some patients with physical features resembling acromegaly - usually affecting the face and extremities -, or gigantism - accelerated growth/tall stature - will have no abnormalities in the GH axis. This scenario is termed pseudoacromegaly, and its correct diagnosis can be challenging due to the rarity and variability of these conditions, as well as due to significant overlap in their characteristics. In this review we aim to provide a comprehensive overview of pseudoacromegaly conditions, highlighting their similarities and differences with acromegaly and pituitary gigantism, to aid physicians with the diagnosis of patients with pseudoacromegaly., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tall stature is not a common motive for medical consultation, even though by definition 2.5 % of children in the general population are concerned. It is usually defined as height greater than+2 standard deviations (SD) using the appropriate growth chart for age and gender, or a difference greater than +2 SD between actual height and target height. With a patient presenting tall stature, the physician has to determine whether it is a benign feature or a disease. Indeed, making the diagnosis is essential for hormonal disease or genetic overgrowth syndromes. The past medical history including parents' height, prenatal and birth data, physical examination along with anthropometry (height, weight, head circumference, body mass index), and growth chart evaluation with the detailed growth pattern are generally sufficient to make the diagnosis such as familial tall stature, obesity, or early puberty. Bone age estimation may be helpful for some specific etiologies and is also necessary to help predict final adult height. After exclusion of common causes, further investigation is required. Sudden growth acceleration often reveals endocrine pathology such as early puberty, hyperthyroidism, or acrogigantism. Tall stature accompanied by dysmorphic features, congenital malformations, developmental delay, or a family medical history may be related to genetic disorders such as Marfan, Sotos, or Wiedemann-Beckwith syndromes. We relate here the most frequent etiologies of overgrowth syndromes., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner., Materials and Methods: We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea. We applied targeted exome sequencing using the Next Seq platform and a TruSight One panel., Results: Among the 13 families, 6 different disorders in 8 patients with short stature or overgrowth were identified, and the diagnostic yield was 46.2%. One boy with overgrowth had a TGFB3 gene mutation. In the short stature group, Coffin-Lowry syndrome (CLS), trichorhinophalangeal syndrome, DYRK1A haploinsufficiency syndrome, short stature with optic atrophy and Pelger-Huët anomaly syndrome with recurrent hepatitis, and type 4 Meier-Gorlin syndrome were identified. One CLS patient had a co-existing monogenic disease, congenital glaucoma, caused by the compound heterozygote mutations of the CYP1B1 gene., Conclusion: Targeted exome sequencing is a powerful method for diagnosing syndromic growth disorders. It enables us to understand molecular pathophysiology and investigate new treatments for growth disorders., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Mutations in the aryl hydrocarbon receptor-interacting protein ( AIP ) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events., Design and Methods: Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP -region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments., Results: Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the 'English founder', with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9-113 generations, equivalent to 225-2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability., Conclusions: The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein-protein interactions and AIP protein stability., (© 2017 The authors.)

Referral for an assessment of tall stature is less common than for short stature. Tall stature is defined as a height more than two standard deviations above the mean for age. The majority of subjects with tall stature show a familial tall stature or a constitutional advance of growth (CAG), which is a diagnosis of exclusion. After a careful physical evaluation, tall subjects may be divided into two groups: tall subjects with normal appearance and tall subjects with abnormal appearance. In the case of normal appearance, the paediatric endocrinologist will have to evaluate the growth rate. If it is normal for age and sex, the subject may be classified as having familial tall stature, CAG or obese subject, while if the growth rate is increased it is essential to evaluate pubertal status and thyroid status. Tall subjects with abnormal appearance and dysmorphisms can be classified into those with proportionate and disproportionate syndromes.A careful physical examination and an evaluation of growth pattern are required before starting further investigations. Physicians should always search for a pathological cause of tall stature, although the majority of children are healthy and they generally do not need treatment to cease growth progression.The most accepted and effective treatment for an excessive height prediction is inducing puberty early and leading to a complete fusion of the epiphyses and achievement of final height, using testosterone in males and oestrogens in females. Alternatively, the most common surgical procedure for reducing growth is bilateral percutaneous epiphysiodesis of the distal femur and proximal tibia and fibula.This review aims to provide up-to-date information and suggestions about the diagnosis and management of children with tall stature.

BACKGROUND Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked recessive syndrome characterized by fetal overgrowth. CASE REPORT We present a case of a male infant with SGBS. Abnormal prenatal ultrasound (including congenital diaphragmatic hernia) prompted microarray testing of amniotic fluid cells, which showed deletion on chromosome Xq26.2 affecting the glypican-3 gene consistent with SGBS type I. The infant died six hours after birth and at autopsy showed features of SGBS, including macrosomia, organomegaly, diaphragmatic hernia with consequent pulmonary hypoplasia, cleft palate, large tongue with a midline groove, a supernumerary nipple, Meckel's diverticulum, and abnormal phalanges. Additionally, we observed features that have previously not been described in SGBS, including testes with hyperplastic seminiferous tubules and Mullerian remnants, and placenta with incipient fetal thrombotic vasculopathy. CONCLUSIONS While most patients with SGBS type I survive into childhood or even adulthood, the severe course in our patient was ascribed to pulmonary hypoplasia secondary to the bilateral diaphragmatic hernia.

The diagnostic approach to tall stature in children is based on collecting birth data (macrosomia), sizes and family puberty, a family history of constitutional or pathological tall stature, search for a delay of development, dysmorphia, disproportion, analysis of the growth velocity (normal or accelerated), general examination and assessment of puberty, and bone age. When there is a history of psychomotor retardation, a family history of pathological tall stature, or a disproportion in the clinical examination, the genetic causes of tall stature will be mentioned. The most frequent causes are Marfan syndrome and similar, Sotos syndrome, Beckwith-Wiedemann syndrome, Klinefelter syndrome, and MEN2B. There are many genetic syndromes with tall stature, justifying consultation with the geneticist. When the speed of growth is accelerated, first of all it evokes puberty and early pseudopuberty, obesity and acromegaly. Finally, when the growth velocity is regular, and the parents are of tall stature, it evokes constitutional tall stature: this is the most frequent diagnosis, to retain after having rejected pathological tall statures., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Acromegaly is a rare and underdiagnosed disorder caused, in more than 95% of cases, by a growth hormone (GH)-secreting pituitary adenoma. The GH hypersecretion leads to overproduction of insulin-like growth factor 1 (IGF-1) which results in a multisystem disease characterized by somatic overgrowth, multiple comorbidities, physical disfigurement, and increased mortality., Objective: This article aims to review the clinical features of acromegaly at diagnosis., Discussion/conclusion: Acromegaly affects both males and females equally and the average age at diagnosis ranges from 40 to 50 years (up to 5% of cases < the age 20). Due to insidious onset and slow progression, acromegaly is often diagnosed five to more than ten years after its onset. The typical coarsening of facial features include furrowing of fronthead, pronounced brow protrusion, enlargement of the nose and the ears, thickening of the lips, skin wrinkles and nasolabial folds, as well as mandibular prognathism that leads to dental malocclusion and increased interdental spacing. Excessive growth of hands and feet (predominantly due to soft tissue swelling) is present in the vast majority of acromegalic patients. Gigantism accounts for up to 5% of cases and occurs when the excess of GH becomes manifest in the young, before the epiphyseal fusion. The disease also has rheumatologic, cardiovascular, respiratory, neoplastic, neurological, and metabolic manifestations which negatively impact its prognosis and patients quality of life. Less than 15% of acromegalic patients actively seek medical attention for change in appearance or enlargement of the extremities. The presentation of acromegaly is more often related to its systemic comorbidities or to local tumor effects.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304 * (or p.R304 * ; NM&#95;003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304 * carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304 * prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304 * is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease., (© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)

Simpson-Golabi-Behmel syndrome is an X-linked recessive overgrowth condition caused by alterations in GPC3 gene, encoding for the cell surface receptor glypican 3, whose clinical manifestations in affected males are well known. Conversely, there is little information regarding affected females, with very few reported cases, and a clinical definition of this phenotype is still lacking. In the present report we describe an additional case, the first to receive a primary molecular diagnosis based on strong clinical suspicion. Possible explanations for full clinical expression of X-linked recessive conditions in females include several mechanisms, such as skewed X inactivation or homozygosity/compound heterozygosity of the causal mutation. Both of these were excluded in our case. Given that the possibility of full expression of SGBS in females is now firmly established, we recommend that GPC3 analysis be performed in all suggestive female cases. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Recently, germline variants of the transcriptional co-regulator gene TCF20 have been implicated in the aetiology of autism spectrum disorders (ASD). However, the knowledge about the associated clinical picture remains fragmentary. In this study, two individuals with de novo TCF20 sequence variants were identified in a cohort of 313 individuals with intellectual disability of unknown aetiology, which was analysed by whole exome sequencing using a child-parent trio design. Both detected variants - one nonsense and one frameshift variant - were truncating. A comprehensive clinical characterisation of the patients yielded mild intellectual disability, postnatal tall stature and macrocephaly, obesity and muscular hypotonia as common clinical signs while ASD was only present in one proband. The present report begins to establish the clinical picture of individuals with de novo nonsense and frameshift variants of TCF20 which includes features such as proportionate overgrowth and muscular hypotonia. Furthermore, intellectual disability/developmental delay seems to be fully penetrant amongst known individuals with de novo nonsense and frameshift variants of TCF20, whereas ASD is shown to be incompletely penetrant. The transcriptional co-regulator gene TCF20 is hereby added to the growing number of genes implicated in the aetiology of both ASD and intellectual disability. Furthermore, such de novo variants of TCF20 may represent a novel differential diagnosis in the overgrowth syndrome spectrum.

Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth syndrome and it is usually diagnosed postnatally, on the basis of phenotype. Prenatal ultrasonography may show fetal alterations, but they are not pathognomonic and most of them are frequently detectable only from the 20th week of gestation. Nevertheless, early diagnosis is important to avoid neonatal complications and make timely and informed decisions about the pregnancy. We report on four fetuses from two unrelated families, in whom the application of whole exome sequencing and array-CGH allowed the identification of GPC3 alterations causing SGBS. The careful follow up of pregnancies and more sophisticated analysis of ultrasound findings led to the identification of early prenatal alterations, which will improve the antenatal diagnosis of SGBS. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objective: Simpson-Golabi-Behmel (SGBS) syndrome type 1 and type 2 represent rare X-linked prenatal overgrowth disorders. The aim of our study is to describe the prenatal sonographic features as well as the genetic work-up., Method: Retrospective analysis of four cases with a pre- or postnatal diagnosis of SGBS in a single tertiary referral center within a period of 4 years., Results: In the study period, four male fetuses with SGBS were detected. The final diagnosis was made prenatally in three cases. In all cases the second trimester anomaly scan revealed left sided congenital diaphragmatic hernia (CDH) with additional anomalies; three fetuses with SGBS type 1 showed fetal overgrowth. In two of these, whole exome sequencing showed a possible frameshift mutation and a point mutation in the gene GPC3, respectively. In the third case, multiplex ligation-dependent probe amplification (MLPA) revealed a hemizygous duplication of exon 3-7 in the gene GPC3. In the fourth case, SGBS type 2 was confirmed by array comparative genomic hybridization (CGH) of amniotic fluid cells showing a deletion of the gene OFD1., Conclusion: We could demonstrate, that in the presence of a CDH, syndromes of the fetus can be increasingly differentiated by detailed sonography followed by a selective and graded molecular diagnostic using microarray techniques and whole exome sequencing. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)

Familial isolated pituitary adenomas (FIPA) constitute 2-3% of pituitary tumours. AIP is the most commonly mutated gene in FIPA. We herein report a novel germline mutation of the AIP gene in a family with FIPA. We present two patients, a father and his 12-year-old daughter, diagnosed clinically and using laboratory measures with acromegaly-gigantism. Both underwent transsphenoidal hypophyseal surgery for macroadenomas. We initially detected a novel heterozygous germline AIP mutation, c.836G>A (p.W279*), in the father's DNA. We then found the same mutation in his affected daughter. Pituitary adenomas associated with AIP mutations mostly present as FIPA (68%) at an early age (78% occur at <30 years old). They are often growth hormone (GH) - or prolactin - secreting macroadenomas (88%) that have already extended beyond the sella at the time of diagnosis. Acromegalic cases are resistant to somatostatin analogues and multimodal management is frequently essential to control the disease. Our patients had normalized GH/IGF-1 values soon after surgery, although enough time may not have elapsed to reach final cure. While penetrance of the disease can be as low as 10% in FIPA, especially children and young patients with somatotropinoma and prolactinoma should be surveyed for inactivating mutations or deletions in AIP. Determining the causative mutations may be of assistance in early diagnosis, treatment success, and genetic counseling.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked condition characterized by pre and post natal overgrowth, facial malformations, and visceral, skeletal, and neurological anomalies. The physical characteristics of SGBS have been well documented; however there is a lack of description regarding the behavioral phenotype. We report the case of a 6-year-old boy, with confirmed deletion of 6-8 exons of the glypican-3 gene (GPC3) who presents three distinctive findings: the persistence of the craniopharyngeal canal, an immune-allergic specificity, and a scarcely behavioral phenotype consisting in the association of Austim Spectrum Disorder with accompanying mild intellectual disability and language impairments. He also fulfilled the criteria of Attention Deficit Hyperactivity Disorder and Oppositional Defiant Disorder according to DSM 5 criteria. The specificities of the case are discussed in the light of recent pathophysiological data., (© 2015 Wiley Periodicals, Inc.)

Acromegaly and pituitary gigantism are very rare conditions resulting from excessive secretion of growth hormone (GH), usually by a pituitary adenoma. Pituitary gigantism occurs when GH excess overlaps with the period of rapid linear growth during childhood and adolescence. Until recently, its etiology and clinical characteristics have been poorly understood. Genetic and genomic causes have been identified in recent years that explain about half of cases of pituitary gigantism. We describe these recent discoveries and focus on some important settings in which gigantism can occur, including familial isolated pituitary adenomas (FIPA) and the newly described X-linked acrogigantism (X-LAG) syndrome., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Overgrowth syndromes are a heterogeneous group of diseases characterized by focal or generalized overgrowth. Many of the syndromes have overlapping clinical features and it is difficult to diagnose the condition based on clinical features alone. In the present study we report on a patient with overgrowth syndrome where extensive investigation did not reveal the cause of disease. Finally exome sequencing revealed a novel hemizygous single base pair deletion in exon 8 of GPC3 gene (chrX:132670203delA) resulting in a frameshift and creating a new stop codon at 62 amino acids downstream to codon 564 (c.1692delT; p.Leu565SerfsTer63) of the protein. The mutation was confirmed by Sanger sequencing. The mother was found to be heterozygous for the mutation. This variation is not reported in the 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC) and dbSNP databases and the region is conserved across primates. Exome sequencing was helpful in establishing diagnosis of Simpson-Golabi-Behmel syndrome type 1 (SGBS1) in a patient with unknown overgrowth syndrome., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Children with generalized overgrowth syndromes are large at birth, or have excessive postnatal growth. Many of these syndromes are associated with an increase in neoplasia. Consideration of the possibility of overgrowth syndrome in a pediatric patient who presents with increased growth parameters, variable malformations and neurodevelopmental phenotype, and distinctive features, is important for medical management, reproductive counseling, and tumor surveillance for some of the disorders. This review describes the clinical features and surveillance recommendations for the common generalized overgrowth syndromes the pediatrician may encounter. It also provides a glimpse into advances of recent years in understanding the molecular mechanisms responsible for the disrupted growth regulation in these disorders., (Copyright © 2015 Mosby, Inc. All rights reserved.)

Overgrowth syndromes with vascular anomalies encompass entities with a vascular anomaly as the predominant feature vs those syndromes with predominant somatic overgrowth and a vascular anomaly as a more minor component. The focus of this article is to categorize these syndromes phenotypically, including updated clinical criteria, radiologic features, evaluation, management issues, pathophysiology, and genetic information. A literature review was conducted in PubMed using key words "overgrowth syndromes and vascular anomalies" as well as specific literature reviews for each entity and supportive genetic information (e.g., somatic mosaicism). Additional searches in OMIM and Gene Reviews were conducted for each syndrome. Disease entities were categorized by predominant clinical features, known genetic information, and putative affected signaling pathway. Overgrowth syndromes with vascular anomalies are a heterogeneous group of disorders, often with variable clinical expression, due to germline or somatic mutations. Overgrowth can be focal (e.g., macrocephaly) or generalized, often asymmetrically (and/or mosaically) distributed. All germ layers may be affected, and the abnormalities may be progressive. Patients with overgrowth syndromes may be at an increased risk for malignancies. Practitioners should be attentive to patients having syndromes with overgrowth and vascular defects. These patients require proactive evaluation, referral to appropriate specialists, and in some cases, early monitoring for potential malignancies. Progress in identifying vascular anomaly-related overgrowth syndromes and their genetic etiology has been robust in the past decade and is contributing to genetically based prenatal diagnosis and new therapies targeting the putative causative genetic mutations., (Copyright © 2015 Mosby, Inc. All rights reserved.)

Background: The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth condition characterised by macrosomia, mental deficiency, large head, prominent skull sutures, midface deficiency, hypertelorism, broad nose, wide mouth, macroglossia, malocclusion, highly arched palate, and musculoskeletal and limb abnormalities. The aim of this case report is to present clinical and oral findings of an 8-year-old boy who had been diagnosed with SGBS., Case Report: This patient had supernumerary nipples on the right side, cubitus valgus webbed fingers, scoliosis, umbilical hernia, a coarse face, macrocephaly, hypertelorism, a short broad nose, a wide mouth, a straight facial profile and hearing loss. The patient also had macroglossia, diastemas, over-retained primary tooth, absent mandibular permanent central incisors, and highly arched palate. Lateral cephalometric analysis revealed a large anterior cranial base, a large maxilla and mandible, a large inferior face height, and skeletal Class III jaw relationship., Follow-Up: After extraction of the over-retained primary central tooth, a partial prosthesis was fabricated in order to maintain function. The patient has been recalled regularly at 6-month intervals for 2 years. Over the following years the prosthesis was replaced due to facial growth., Conclusion: Long term follow-up is essential for the patient with SGBS. Preventive dental care, including oral hygiene instructions, diet counselling and the use of fluoride has been implemented.

Clinical overlap makes the diagnosis of overgrowth syndromes challenging. Clinical overlap exists between Simpson-Golabi-Behmel syndrome (SGBS) and Beckwith-Wiedemann syndrome (BWS) which share pre- and postnatal overgrowth, macroglossia, umbilical hernia, organomegaly, ear lobe creases, and occurrence of embryonal tumors as characteristic features. Based on the clinical history of a patient, who was diagnosed with BWS shortly after birth and reassessed and rediagnosed with SGBS at age 21 years, particular attention should be paid to developing facial dysmorphia. In addition, we delineate further clinical findings that may allow differentiation between both conditions., (© 2014 Wiley Periodicals, Inc.)

Simpson-Golabi-Behmel syndrome (SGBS) is a rare overgrowth syndrome clinically characterized by multiple congenital abnormalities, pre/postnatal overgrowth, distinctive craniofacial features, macrocephaly, and organomegaly. Abnormalities of the skeletal system, heart, central nervous system, kidney, and gastrointestinal tract may also be observed. Intellectual disability, early motor milestones and speech delay are sometimes present; however, there are a considerable number of individuals with normal intelligence.