Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy.

CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant. Significant polyhydramnios occurred in 6/7 pregnancies. Severe respiratory compromise was seen in 6/7 (tracheostomy in 5). A complex neurological phenotype was seen in all patients who had marked brain hypomyelination/demyelination and profound developmental delay. Additional neurological findings included cranial nerve compromise: orobulbar dysfunction in 5/7, facial nerve weakness in 4/7 and vocal cord paresis in 5/7. Dystonia occurred in 2/7 patients and limb contractures in 5/7. All had severe gastroesophageal reflux, and a gastrostomy was required in 5/7. In contrast to most previous reports, only one patient died in the first year of life. Protein modelling was performed for all detected CNTNAP1 variants. We propose a genotype-phenotype correlation, whereby hypomorphic missense variants partially ameliorate the phenotype, prolonging survival. This study suggests that biallelic variants in CNTNAP1 cause a distinct recognisable syndrome, which is not caused by other genes associated with CHN. Neonates presenting with this phenotype will benefit from early genetic definition to inform clinical management and enable essential genetic counselling for their families.

Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth.

OBJECTIVE: Barth Syndrome (BTHS) is an X-linked multisystem disorder (OMIM 302060) usually diagnosed in infancy and characterized by cardiac problems [dilated cardiomyopathy (DCM) ± endocardial fibroelastosis (EFE) ± left ventricular non-compaction (LVNC)], proximal myopathy, feeding problems, growth retardation, neutropenia, organic aciduria and variable respiratory chain abnormalities. We wished to determine whether BTHS had a significant impact on fetal and perinatal health in a large cohort of family groups originating from a defined region. METHOD: Case note review on 19 families originating from the UK and known to the Barth Syndrome Service of the Bristol Royal Hospital for Children. RESULTS: Details are presented on six kindreds (32%) with genetically and biochemically proven BTHS that demonstrate a wider phenotype including male fetal loss, stillbirth and severe neonatal illness or death. In these families, 9 males were stillborn and 14 died as neonates or infants but there were no losses of females. BTHS was definitively proven in five males with fetal onset of DCM ± hydrops/EFE/LVNC. CONCLUSION: These findings stress the importance of considering BTHS in the differential diagnosis of unexplained male hydrops, DCM, EFE, LVNC or pregnancy loss, as well as in neonates with hypoglycemia, lactic acidosis and idiopathic mitochondrial disease.

Orthopaedic manifestations and management of spondyloepimetaphyseal dysplasia Strudwick type.

Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type is a rare autosomal dominant condition arising from defects in COL2A1 the genes responsible for the biosynthesis of procollagen type II. The orthopaedic manifestations of patients can be hypoplastic odontoid peg with atlantoaxial instability, severe kyphosis or lordosis of dorsal and lumbar spines, hip subluxation, coxa vara and early severe hip osteoarthritis, and malalignment of lower limbs like genu valgum or club foot. We report a mother and daughter with SEMD Strudwick Type and describe their orthopaedic problems, surgical management and clinical outcome after 30 years and 7 years of follow-up respectively.

An association of multiple well differentiated liposarcomas, lipomatous tissue and hereditary retinoblastoma.

Well differentiated liposarcoma (atypical lipomatous tumour) is a low grade tumour, with no metastatic potential unless dedifferentiation supervenes. When superficial, it recurs locally only occasionally after marginal excision. We present a patient in whom bilateral childhood retinoblastoma was followed by later development of massive confluent areas of low grade liposarcoma and lipomatous tissue affecting the upper extremities and trunk. We discuss the role of mutations in the retinoblastoma gene (RB1) in linking these conditions and demonstrate the surgical management of an extremely unusual and challenging case.

Diagnosis in dysmorphology: clues from the skin.

Dysmorphology is the study of abnormal patterns of human development. A recurrent and recognizable combination of physical and behavioural abnormalities makes up a syndrome. Accurate recognition and diagnosis of syndromes is important because it influences medical management of patients, provides information about prognosis, and allows for genetic counselling including accurate estimation of genetic risk within families and, where possible, prenatal diagnosis. This review examines the diagnostic process in dysmorphology and indicates how skin signs may provide important clues to the clinician.

Siblings with Bohring-Opitz syndrome.

We describe a brother and sister with Bohring-Opitz syndrome and suggest that autosomal recessive inheritance may occur in this condition.

The KBG syndrome.

We report on two boys with a combination of short stature, a broad face, macrodontia and developmental delay. These features suggest that they have the KBG syndrome, a rare but distinctive phenotype. The pattern of inheritance remains uncertain and both autosomal dominant and X-linked recessive inheritance should be considered in genetic counselling.