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The femoral facial syndrome (FFS) is a rare congenital anomaly syndrome characterized by bilateral femoral hypoplasia and facial dysmorphism. The etiology of FFS is currently unknown but maternal/gestational diabetes has been proposed as a strong risk factor for syndromic femoral hypoplasia. In affected children born to non-diabetic mothers, a genetic contribution to FFS is suspected; however, no chromosomal anomalies or gene mutations have been identified so far. Here, we report on a girl with FFS and a de novo complex chromosome rearrangement of terminal chromosome 2q37.2. Radiographs of the pelvis and lower limbs showed bilateral shortening and bowing of the femur and radiographs of hands and feet revealed a brachydactyly type E (BDE). Using high resolution array-CGH, qPCR, and FISH, we detected a ~1.9 Mb duplication in the chromosomal region 2q37.2 and a ~5.4 Mb deletion on chromosome 2q37.3 that were absent in the parents. The duplication contains six genes and the deletion encompasses 68 genes; the latter has previously been shown to cause BDE (through haploinsufficiency for HDAC4) but not femoral hypoplasia. Therefore, we propose that the duplication 2q37.2 could be causative for the femur phenotype. To the best of our knowledge, our report is the first to propose a genetic cause in a case of FFS., (© 2016 Wiley Periodicals, Inc.)

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (lepto-SEMDJL, aka SEMDJL, Hall type), is an autosomal dominant skeletal disorder that, in spite of being relatively common among skeletal dysplasias, has eluded molecular elucidation so far. We used whole-exome sequencing of five unrelated individuals with lepto-SEMDJL to identify mutations in KIF22 as the cause of this skeletal condition. Missense mutations affecting one of two adjacent amino acids in the motor domain of KIF22 were present in 20 familial cases from eight families and in 12 other sporadic cases. The skeletal and connective tissue phenotype produced by these specific mutations point to functions of KIF22 beyond those previously ascribed functions involving chromosome segregation. Although we have found Kif22 to be strongly upregulated at the growth plate, the precise pathogenetic mechanisms remain to be elucidated., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The facial photographs of 81 individuals with Noonan syndrome, from infancy to adulthood, have been evaluated by two dysmorphologists (JA and MZ), each of whom has considerable experience with disorders of the Ras/MAPK pathway. Thirty-two of this cohort have PTPN11 mutations, 21 SOS1 mutations, 11 RAF1 mutations, and 17 KRAS mutations. The facial appearance of each person was judged to be typical of Noonan syndrome or atypical. In each gene category both typical and unusual faces were found. We determined that some individuals with mutations in the most commonly affected gene, PTPN11, which is correlated with the cardinal physical features, may have a quite atypical face. Conversely, some individuals with KRAS mutations, which may be associated with a less characteristic intellectual phenotype and a resemblance to Costello and cardio-facio-cutaneous syndromes, can have a very typical face. Thus, the facial phenotype, alone, is insufficient to predict the genotype, but certain facial features may facilitate an educated guess in some cases.

Cardio-facio-cutaneous (CFC) and Costello syndrome (CS) are congenital disorders with a significant clinical overlap. The recent discovery of heterozygous mutations in genes encoding components of the RAS-RAF-MAPK pathway in both CFC and CS suggested a similar underlying pathogenesis of these two disorders. While CFC is heterogeneous with mutations in BRAF, MAP2K1, MAP2K2 and KRAS, HRAS alterations are almost exclusively associated with CS. We carried out a comprehensive mutation analysis in 51 CFC-affected patients and 31 individuals with CS. Twelve different BRAF alterations were found in twenty-four patients with CFC (47.0%), two MAP2K1 mutations in five (9.8%) and two MAP2K2 sequence variations in three CFC-affected individuals (5.9%), whereas three patients had a KRAS alteration (5.9%). We identified four different missense mutations of HRAS in twenty-eight cases with CS (90.3%), while KRAS mutations were detected in two infants with a phenotype meeting criteria for CS (6.5%). In 14 informative families, we traced the parental origin of HRAS alterations and demonstrated inheritance of the mutated allele exclusively from the father, further confirming a paternal bias in the parental origin of HRAS mutations in CS. Careful clinical evaluation of patients with BRAF and MAP2K1/2 alterations revealed the presence of slight phenotypic differences regarding craniofacial features in MAP2K1- and MAP2K2-mutation positive individuals, suggesting possible genotype-phenotype correlations.

Oculo-auriculo-vertebral spectrum (OMIM164210) is a phenotypically and probably also a genetically heterogeneous disorder, characterized by anomalies of the ear (mostly microtia), hemifacial microsomia, and defects of the vertebral column. Associated clinical findings include anomalies of the eye and brain, and developmental delay. We have evaluated the clinical data and photographs of 53 unrelated patients with OAVS, all presenting with either isolated microtia or preauricular tags in association with hemifacial microsomia as minimal diagnostic criteria; five had a positive family history for OAVS. Based on the main clinical findings and unilateral or bilateral involvement, we have developed a new classification system for OAVS, consisting of six subgroups. There is a statistically significant correlation between the subgroup and number of associated clinical findings, and a statistically significant difference regarding prognosis in uni- and bilaterally affected patients, suggesting that this classification is clinically relevant to the categorization of patients with OAVS. The newly developed scoring system (two points for each main clinical finding and one for each associated clinical finding) presented here, also aids prognosis, especially for delay of motor development and brain anomalies, and statistical analysis revealed significant clustering between different clinical findings of OAVS confirming the clinical impression previously published by several authors.

Townes-Brocks syndrome is an autosomal dominantly inherited disorder, which comprises multiple birth defects including renal, ear, anal, and limb malformations. TBS has been shown to result from mutations in SALL1, a human gene related to the developmental regulator SAL of Drosophila melanogaster. The SALL1 gene product is a zinc finger protein thought to act as a transcription factor. It contains four highly conserved, evenly distributed C2H2 double zinc finger domains. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL1 contains a C2HC motif. Most mutations causing TBS are clustered in the N-terminal third of the SALL1 coding region and result in the production of truncated proteins containing only one or none of the C2H2 domains and the N-terminal transcriptional repressor domain of SALL1. Twenty-three SALL1 mutations were reported prior to this work, 22 of which are located in exon 2, 5' of the second double zinc finger-encoding region. Here we present 12 novel mutations in SALL1 associated with Townes-Brocks syndrome in 13 unrelated families. These include three nonsense mutations, three short insertions and six short deletions. Thus the number of SALL1 mutations increases to 35. Rare phenotypical features among mutation positive patients include hypothyroidism, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, dorsal hypoplasia of the corpus callosum, and umbilical hernia.

The Shprintzen-Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective-tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down-slanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed.

We describe a male patient with lobar holoprosencephaly, ectrodactyly, and cleft lip/palate, a syndrome which has been seen previously in only six patients. In addition, our patient developed hypernatraemia, which has been described in three patients before.

We present 2 sibs with manifestations of oral-facial-digital syndromes (OFD) and Joubert syndrome. The index patient was the 5th child of healthy nonconsanguineous Turkish parents. At birth this female patient had large hydrocephalus, hypertelorism, deep-set eyes, nystagmus, broad mouth, thick oral frenula, cleft palate, hamartomas of the tongue, postaxial polydactyly of fingers, normal toes, and hypotonia. Cranial MRI showed hydrocephalus and Dandy-Walker malformation. The child had no psychomotor development, was unable to swallow and had severe seizures. She died at 2 months of recurrent apneic episodes. At birth the brother of the index patient showed prominent forehead, broad, deep nasal bridge, cleft palate, multiple hamartomas of the tongue, irregular alveolar ridges, retrognathia, bilateral postaxial polydactyly of the hands and feet, and broad halluces. He had an abnormal breathing pattern with phases of tachypnea and apnea. Cranial MRI showed hydrocephalus, hypoplasia of the cerebellar vermis, Dandy-Walker malformation, and hypomyelination of the corpus callosum. Renal ultrasonography demonstrated multiple small cysts. Ocular fixation was absent and he had a mild nystagmus., (Copyright 2000 Wiley-Liss, Inc.)

Esophageal atresia (EA) is a common life-threatening congenital anomaly that occurs in 1/3,000 newborns. Little is known of the genetic factors that underlie EA. Oculodigitoesophageoduodenal (ODED) syndrome (also known as "Feingold syndrome") is a rare autosomal dominant disorder with digital abnormalities, microcephaly, short palpebral fissures, mild learning disability, and esophageal/duodenal atresia. We studied four pedigrees, including a three-generation Dutch family with 11 affected members. Linkage analysis was initially aimed at chromosomal regions harboring candidate genes for this disorder. Twelve different genomic regions covering 15 candidate genes (approximately 15% of the genome) were excluded from involvement in the ODED syndrome. A subsequent nondirective mapping approach revealed evidence for linkage between the syndrome and marker D2S390 (maximum LOD score 4.51 at recombination fraction 0). A submicroscopic deletion in a fourth family with ODED provided independent confirmation of this genetic localization and narrowed the critical region to 7.3 cM in the 2p23-p24 region. These results show that haploinsufficiency for a gene or genes in 2p23-p24 is associated with syndromic EA.

Greig cephalopolysyndactyly syndrome (GCPS, MIM 175700) is a rare autosomal dominant developmental disorder characterized by craniofacial abnormalities and post-axial and pre-axial polydactyly as well as syndactyly of hands and feet. Human GLI3, located on chromosome 7p13, is a candidate gene for the syndrome because it is interrupted by translocation breakpoints associated with GCPS. Since hemizygosity of 7p13 resulting in complete loss of one copy of GLI3 causes GCPS as well, haploinsufficiency of this gene was implicated as a mechanism to cause this developmental malformation. To determine if point mutations within GLI3 could be responsible for GCPS we describe the genomic sequences at the boundaries of the 15 exons and primer pair sequences for mutation analysis with polymerase chain reaction-based assays of the entire GLI3 coding sequences. In two GCPS cases, both of which did not exhibit obvious cytogenetic rearrangements, point mutations were identified in different domains of the protein, showing for the first time that Greig syndrome can be caused by GLI3 point mutations. In one case a nonsense mutation in exon X generates a stop codon truncating the protein in the C-H link of the first zinc finger. In the second case a missense mutation in exon XIV causes a Pro-->Ser replacement at a position that is conserved among GLI genes from several species altering a potential phosphorylation site.

Unlabelled: Microgastria is a rare malformation of the stomach always associated with variable patterns of malformations of the lung, heart, aortic arch, skeleton, and central nervous system. Many cases present with asplenia and hepatic symmetry as well as intestinal malrotation. We report a first case of a 4.5-year-old girl with congenital microgastria in association with growth hormone deficiency, diabetes insipidus, brachyoesophagus, hernia of the diaphragm, gastro-oesophageal reflux, intestinal malrotation, enlarged symmetrical liver, asplenia, as well as mental and statomotor retardation., Conclusion: Congenital microgastria is always associated with malformations of other organs. Patients at any age presenting one of the symptoms: failure to thrive, vomiting, asplenia, midline defects and parts of the VACTERL association should be carefully examined to exclude microgastria.

Osteopathia striata is a manifestation of several bone dysplasias. In association with cranial sclerosis it represents a separate entity, which is not limited to the bones but may affect other structures, leading to abnormal face, cleft palate, deafness, heart defects, and vertebral anomalies. Neurological findings range from normal development to marked retardation with hydrocephalus, cranial nerve deficiencies and deafness. Ten families, including our own, clearly demonstrate autosomal dominant inheritance with female preponderance and great inter- and intrafamilial variability.

The Schimmelpenning-Feuerstein-Mims-syndrome includes deformities and dysplasias of the skin, eyes, brain, skeleton, and heart. It may result from a malformation of the ectodermal and mesodermal blastoderm in the third week of gestation. We here report on 6 patients who presented between 1977 and 1993 in comparison with those cases in the literature. All children presented neurologic symptoms. The major symptom was a linear epidermal nevus. In addition we found mental retardation, convulsions, asymmetries of the cranial structures or dilated cerebral ventricles ipsilateral to the nevus. One child had a defect of the skull and scalp, a symptom not previously mentioned in the literature. Our patients exhibited a wide phenotypice spectrum ranging from mild to severe forms. Severe neurological symptoms were also found in patients despite minimal dermal involvement.

A five-generation family with the branchio-oto-renal (BOR) syndrome is reported demonstrating the great variability of this syndrome. Symptoms of the branchio-oto, branchio-oto-ureteral, and BOR syndromes are seen in different members of this family, suggesting that these are not real entities, but variants of the BOR syndrome.

The Kabuki (Niikawa-Kuroki) syndrome was reported in 1981 by Niikawa et al. and Kuroki et al. in a total of ten unrelated Japanese children with a characteristic array of multiple congenital anomalies and mental retardation. The syndrome is characterized by a distinct face, mild to moderate mental retardation, postnatal growth retardation, dermatoglyphic and skeletal abnormalities. In Japan, the syndrome appears to have an incidence of about 1:32,000 newborns. Outside of Japan, a growing number of patients have been recognized. Clinical data are presented on 29 Caucasian patients; the patients were diagnosed over a relatively short period of time, indicating that the incidence outside of Japan is probably not lower than in Japan. A literature review of 89 patients (60 Japanese and 29 non-Japanese) is given. In 66% of the non-Japanese patients serious neurological problems were present, most notably hypotonia and feeding problems (which were not only related to the cleft palate); this was not reported in the Japanese patients. Inheritance is not clear. Most patients are isolated, sex-ratio is equal. The syndrome can be recognized in patients with cleft (lip/)palate, with mild to moderate developmental delay and in young children with hypotonia and/or feeding problems. In counselling parents, the designation "Kabuki" syndrome seems to be more appropriate than "Kabuki make-up" syndrome.

We report on a family with 2 affected males with the X-linked Simpson-Golabi-Behmel (SGB) syndrome. The propositus was a 33-year-old man with pre- and postnatal overgrowth, "coarse" face with hypertelorism, broad nose, wide mouth, malposition of teeth, submucous cleft, accessory nipples, broad hands with hypoplastic index finger nails, and operated left postaxial hexadactyly. From the age of 26 years he suffered from severe tachyarrhythmias, requiring recurrent defibrillations. The brother of the propositus was macrosomic at birth and had a similar facial appearance. In addition he had a pyloric stenosis and a 3/6 systolic murmur. He died at age 4 months. Cardiac defects and conduction disturbances are major components of the SBG syndrome and can be responsible for death in early infancy and perhaps for cardiac arrest in the adult.