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Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive disorder caused by mutations in RECQL4 and has characteristic clinical features. We report two unrelated phenotypically diverse patients (cases 1 and 2) with RTS having novel variants in RECQL4 gene. Case-1 was evaluated for poor growth and recurrent fractures and skin lesions. Case-2 presented at 4 months with failure to thrive and radial ray defect and developed poikilodermatous skin lesions after infancy. Both cases were confirmed to have homozygous pathogenic variants in RECQL4. Both patients have normal intellect and are on supportive therapy. The presence of characteristic poikiloderma lesions with specific distribution and skeletal anomalies in a patient with proportionate short stature is a clue toward the diagnosis of RTS.

A 3-year-old boy presented with acute corneal hydrops on the left eye and spontaneous corneal rupture on the right eye. A diagnosis of brittle cornea syndrome was confirmed by molecular analysis. A novel mutation, the homozygous variant c.17T>G, p.V6G, was found in the gene for PR-domain-containing protein 5 (PRDM5) in exon 1. Brittle cornea syndrome is a rare connective tissue disease with typical ocular, auditory, musculoskeletal, and cutaneous disorders. Almost all patients suffer from declined vision due to corneal scarring, thinning, and rupture. The most common ophthalmologic findings include keratoconus, progressive central corneal thinning, high myopia, irregular astigmatism, retinal detachment, and high risk for spontaneous corneal or scleral rupture. In addition to describing the case with a novel mutation here we review the current literature on brittle cornea syndrome pathogenesis, clinical findings, and therapy.

Paroxysmal kinesigenic dyskinesia (PKD) (MIM 128200) is a rare paroxysmal movement disorder that occurs at an estimated prevalence of 1:150,000 individuals. 1 Onset is most commonly in childhood or adolescence, with sporadic and familial cases being reported. 2,3 PKD is characterized by short and frequent episodes of dystonic or choreiform movements that are precipitated by sudden voluntary movements or startle. Classic clinical criteria for PKD therefore include an identifiable kinesigenic trigger, short duration of attacks, no loss of consciousness or pain during attacks, normal interictal neurologic examination results, the exclusion of other organic diseases, onset between 1 and 20 years of age (if no family history), and a response to treatment with anticonvulsants (sodium channel blockers). 3 Genetically, most cases

The increased use of array-CGH and SNP-arrays for genetic diagnosis has led to the identification of new microdeletion/microduplication syndromes and enabled genotype-phenotype correlations to be made. In this study, nine patients with 9q21 deletions were investigated and compared with four previously Decipher reported patients. Genotype-phenotype comparisons of 13 patients revealed several common major characteristics including significant developmental delay, epilepsy, neuro-behavioural disorders and recognizable facial features including hypertelorism, feature-less philtrum, and a thin upper lip. The molecular investigation identified deletions with different breakpoints and of variable lengths, but the 750 kb smallest overlapping deleted region includes four genes. Among these genes, RORB is a strong candidate for a neurological phenotype. To our knowledge, this is the first published report of 9q21 microdeletions and our observations strongly suggest that these deletions are responsible for a new genetic syndrome characterised by mental retardation with speech delay, epilepsy, autistic behaviour and moderate facial dysmorphy.

Introduction The prevalence of neural tube defects worldwide is 1 – 2 per 1000 neonates. Neural tube defects result from a disturbance of neurulation in the 3rd or 4th week of development and thus represent the earliest manifestation of organ malformation. Neural tube defects (NTD) are classified into cranial dysraphism leading to anencephaly or meningoencephalocele and spinal dysraphism with or without meningomyelocele. In isolated form they have multifactorial causes, and the empirical risk of recurrence in Central Europe is 2%. As associated malformations they tend to occur sporadically, and in monogenic syndromes they follow Mendelian inheritance patterns with a high risk of recurrence. Patients Autopsies were performed on 68 fetuses following a prenatal diagnosis of NTD and induced abortion. Results The incidence of NTDs in our autopsied fetuses was 8% and 11% in fetuses with malformations. The percentage of fetuses with anencephaly, encephalocele or spina bifida was 24, 18, and 60%*, respectively. Analysis of the sex distribution showed a female preponderance in cranial dysraphisms but the sex distribution of spina bifida cases was equal. The extent and localization of NTDs varied, with lumbosacral cases clearly predominating. The proportion of isolated, associated and syndromic neural tube defects was 56, 23.5 and 20.6% respectively. In the majority of syndromes, the neural tube defect represented a not previously observed syndromic feature. Conclusion The high proportion of NTDs with monogenic background underlines the importance of a syndrome oriented fetal pathology. At the very least it requires a thourough photographic and radiographic documentation of the fetal phenotype to enable the genetic counsellor to identify a syndromic disorder. This is necessary to determine the risk of recurrence, arrange confirming mutation analyses and offer targeted prenatal diagnosis in subsequent pregnancies.

Objective Fetal pathology aims to recognize syndromal patterns of anomalies for goal-directed mutation analyses, genetic counseling, and early prenatal diagnosis in consecutive pregnancies. Here, we report on five fetuses with Peters' plus syndrome (PPS) from two distinct families aborted after prenatal ultrasound diagnosis of hydrocephaly. Method We performed fetal autopsies and molecular analyses. Results Among 44 fetuses with prenatally diagnosed hydrocephaly, four fetuses of 16 to 21 gestational weeks presented with additional cleft lip/palate and/or agenesis of the corpus callosum. Other features were growth retardation, hypertelorism, anomalies of the eyes, in part consistent with Peters' anterior chamber anomalies, mild brachymelia, brachydactyly, and also internal anomalies. Suspected PPS was confirmed by detection of B3GALTL mutation in these four fetuses and in one additional sib fetus, revealing homozygosity for the common c.660 + 1G > A donor splice site mutation in intron 8. Conclusions Autosomal-recessive PPS has not yet been diagnosed prenatally. We want to alert ultrasonographers to the diagnosis of this disorder in growth-retarded fetuses with (recurrent) hydrocephaly, agenesis of the corpus callosum, and cleft lip/palate and stress the more severe fetal manifestation, describing a first such case with additional Dandy-Walker cyst and occult meningoencephalocele.

Townes-Brocks syndrome (TBS) is a condition with imperforate anus, hand anomalies, and ear malformations with sensorineural hearing loss. Many cases are sporadic. Within and between families, the phenotype displays striking variability. Recently, the disease-causing gene for TBS was identified as SALL1, a zinc finger transcription factor. Here, we report a three-generation family with seven affected individuals who have a novel SALL1 mutation. Unique cardiac anomalies seen in this family include lethal truncus arteriosus in one patient and a lethal complicated defect, including pulmonary valve atresia, in a second patient. These severe cardiac anomalies have not previously been reported in a familial case of TBS. This family and a review of the literature indicate that cardiac evaluation is warranted in all individuals with this disorder. In addition, hypoplastic thumbs were seen in two individuals in this family and should, therefore, be considered a true feature of TBS.

Determining the precise cause of adrenal insufficiency occurring in infancy is of critical importance for both the correct management of affected children and the provision of correct genetic advice to their families. We report a case of a 24-year-old, male patient bearing a new mutation in the DAX1 gene. The patient was born at term, from a healthy pregnancy. Adrenal insufficiency was diagnosed in the fourth week of life with a salt-wasting syndrome, but it was mistakenly believed to be secondary to congenital adrenal hyperplasia (CAH). On hydrocortisone substitution, the child continued to develop normally, but the diagnosis of CAH was questioned, which led to an episode of an abrupt withdrawal of hydrocortisone substitution and subsequently caused a reoccurrence of a life-threatening salt-wasting syndrome. Owing to close follow-up, the patient's gonadal axis deficiency was promptly identified, which allowed an assisted but successful onset of puberty. We proposed the diagnosis of adrenal hypoplasia congenita (AHC) in this patient and identified a hemizygous mutation (c.1130delAinsGT, p.E377GfsX12) in exon 1 of the NR0B1 gene. To our knowledge, the detected mutation has not been described previously (HGMD Professional 2010.4, Human Gene Mutation Database, Biobase, Beverly, MA, USA). It leads to a frameshift, a premature stop codon, and, most likely, non-sense-mediated decay of the mutant mRNA. In this case, close patient follow-up minimized the detrimental consequences of an incorrect diagnosis. Nevertheless, it highlights the importance of the early precise diagnosis of patients with AHC.