Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome.

BACKGROUND: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, ß 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. RESULTS: We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. CONCLUSIONS: These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.

Hypohidrotic and anhidrotic ectodermal dysplasia (HED/EDA) is a rare genodermatosis characterized by abnormal development of sweat glands, teeth, and hair. Three disease-causing genes have been hitherto identified, namely, (1) EDA1 accounting for X-linked forms, (2) EDAR, and (3) EDARADD, causing both autosomal dominant and recessive forms. Recently, WNT10A gene was identified as responsible for various autosomal recessive forms of ectodermal dysplasias, including onycho-odonto-dermal dysplasia (OODD) and Schöpf-Schulz-Passarge syndrome. We systematically studied EDA1, EDAR, EDARADD, and WNT10A genes in a large cohort of 65 unrelated patients, of which 61 presented with HED/EDA. A total of 50 mutations (including 32 novel mutations) accounted for 60/65 cases in our series. These four genes accounted for 92% (56/61 patients) of HED/EDA cases: (1) the EDA1 gene was the most common disease-causing gene (58% of cases), (2)WNT10A and EDAR were each responsible for 16% of cases. Moreover, a novel disease locus for dominant HED/EDA mapped to chromosome 14q12-q13.1. Although no clinical differences between patients carrying EDA1, EDAR, or EDARADD mutations could be identified, patients harboring WNT10A mutations displayed distinctive clinical features (marked dental phenotype, no facial dysmorphism), helping to decide which gene should be first investigated in HED/EDA.

Clinical and histologic features of incontinentia pigmenti in adults with nuclear factor-κB essential modulator gene mutations.

BACKGROUND: Incontinentia pigmenti (IP) is a multisystem disorder, in which cutaneous symptoms can be accompanied by dental, ocular, and central nervous system defects. In adults, the clinical diagnosis of IP is based principally on the late onset of stage 4 lesions and their association with dental, nail, ocular, or central nervous system anomalies. Nevertheless, these lesions are often unrecognized. OBJECTIVES: Our aim was assessment of IP manifestations in adults to clarify diagnostic criteria for mild forms of the disease, to help physicians detect adult IP in the presence of subtle lesions and avoid misdiagnosis. METHOD: We conducted clinical and histologic examination of 25 adults with IP and nuclear factor-κB essential modulator gene rearrangement or mutations. RESULTS: Linear atrophic, hypopigmented, and hairless lesions (stage 4) are constant in adults. Apoptotic keratinocytes in the epidermis or dermis and atrophic hair follicles, with absence of arrector pili muscles, are frequently observed. In contrast, nipple anomalies are rare. LIMITATIONS: We were unable to determine the age of the onset of IP stage 4 lesions. CONCLUSION: Skin manifestations are constant in adult patients with IP. Histology is characteristic and could be considered as a minor diagnostic criterion of IP. Nipple anomalies also may be considered as a minor criterion. Detection of such subtle manifestations can evoke IP in patients with repeated miscarriages or unexplained neurologic manifestations.

[Variable clinical expression of familial Incontinentia Pigmenti syndrome - presentation of three cases]. / Zróznicowanie ekspresji fenotypowej rodzinne wystepujacego zespolu Incontinentia Pigmenti - prezentacja trzech przypadków.

Incontinentia Pigmenti (IP, Bloch-Sulzberger syndrome, OMIM 308300) is a rare X-linked dominant genodermatosis, usually lethal in males in the prenatal period. Wide spectrum of clinical expression consists of skin hyperpigmented lines and swirling patterns, dysplastic teeth and nails, and in 30% central nervous system abnormalities including seizures, microcephaly and intellectual disability (10% of cases). In 80% of IP cases, the disease is caused by a large-scale deletion of exons 4 to 10 of the NEMO gene. Three cases of variable expression of Incontinentia Pigmenti are presented. In a one-year-old girl, her mother and grandmother molecular analysis revealed the same typical deletion of the NEMO gene. In the proband, characteristic skin lesions were detected located over the trunk and lower limbs. Characteristic evolution of the changes was observed. In the mother, expression of the disease was much milder, whereas in the grandmother lesions were restricted to the fingernails. Clinical characteristics and pedigree data are described.