Pathogenic Variants in GPC4 Cause Keipert Syndrome.

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

Two siblings with triple A syndrome and novel mutation presenting as hereditary polyneuropathy.

The clinical and molecular data on triple A syndrome in two siblings (girl 3.5 years and boy 5.5 years at presentation) with early onset of neurological dysfunction are described. Both patients showed delayed developmental milestones and neurological dysfunctions (motor and sensory demyelinating neuropathy, marked hyperreflexia, calves hypothrophy, pes cavus, gait disturbance) in early childhood, when erroneously diagnosed with hereditary polyneuropathy, most likely Charcot-Marie-Tooth disease. After a severe adrenal crisis in the younger sister at the age of 3 years, the older brother aged 5.5 years was also evaluated and latent adrenal insufficiency was discovered. As both of the siblings had alacrima, hyperkeratosis of palms, cutis anserina, and nasal speech, diagnosis of triple A syndrome was considered. Sequencing of the AAAS gene detected a compound heterozygous mutation consisting of a novel mutation p.Ser296Tyr (c.887C>A) in exon 9 and a previously described p.Ser263Pro (c.787T>C) missense mutation in exon 8 in both siblings. In conclusion, triple A syndrome should be considered in patients presenting with early neurological dysfunction and developmental delay. Alacrima as the earliest and most consistent clinical sign should be investigated by Schirmer test. Patients should be regularly tested for adrenal dysfunction to prevent life-threatening adrenal crises.

[Primary pigmented nodular adrenocortical disease as cause of Cushing's syndrome associated with Carney complex]. / Primarna pigmentna nodularna adrenokortikalna bolest kao uzrok Cushingova sindroma u sklopu Carneyeva kompleksa.

We report a 11-year-old girl and two 14-year-old boys with Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). In these patients, hypercortisolism is a consequence of autonomous cortisol secretion from adrenal glands and is ACTH-independent. Besides PPNAD, the girl had lentigines, spotty pigmentation on her bucal mucosa and lips and she also had schwannoma. One of the reported boys had prolactinoma. Considering this, those two patients fulfill the criteria for Carney complex which is a type of multiple endocrine neoplasia syndromes inherited in an autosomal dominant trait. The other boy had PPNAD but no other obvious signs of Carney complex were noticed. Family study didn't reveal any clinical or laboratory signs of Carney complex in our patients' first relatives. All of our patients underwent bilateral adrenalectomy (in one of the boys laparoscopic surgery was performed). Glucocorticoid and mineralocorticoid substitution has been started. Adrenal glands were macroscopically normal but pathohistological analysis confirmed the diagnosis of PPNAD.

Growth hormone positive effects on craniofacial complex in Turner syndrome.

OBJECTIVE: Turner syndrome occurs in phenotypic females with complete or partial absence of X chromosome. The leading symptom is short stature, while numerous but mild stigmata manifest in the craniofacial region. These patients are commonly treated with growth hormone to improve their final height. The aim of this study was to assess the influence of long-term growth hormone therapy on craniofacial morphology in Turner syndrome patients. DESIGN: In this cross-sectional study cephalometric analysis was performed on 13 lateral cephalograms of patients with 45,X karyotype and the average age of 17.3 years, who have received growth hormone for at least two years. The control group consisted of 13 Turner syndrome patients naive to growth hormone treatment, matched to study group by age and karyotype. Sixteen linear and angular measurements were obtained from standard lateral cephalograms. Standard deviation scores were calculated in order to evaluate influence of growth hormone therapy on craniofacial components. RESULTS: In Turner syndrome patients treated with growth hormone most of linear measurements were significantly larger compared to untreated patients. Growth hormone therapy mainly influenced posterior face height, mandibular ramus height, total mandibular length, anterior face height and maxillary length. While the increase in linear measurements was evident, angular measurements and facial height ratio did not show statistically significant difference. Acromegalic features were not found. CONCLUSIONS: Long-term growth hormone therapy has positive influence on craniofacial development in Turner syndrome patients, with the greatest impact on posterior facial height and mandibular ramus. However, it could not compensate X chromosome deficiency and normalize craniofacial features.

Occlusal molar surfaces in females with Turner's syndrome.

The aim of this study was to identify the molar occlusal features in 73 subjects with the Turner's syndrome (TS) and compared to a control group (CG) of 322 healthy females. The occlusal features were scored on dental plaster casts using the Scoring Procedures for Key Morphological Traits of the Permanent Dentition: The Arizona State University Dental Anthropology System (ASU). The results were analyzed through frequency, percentage and chi 2-test. TS subjects have more frequent reduction of cusp number, distolingual cusp on the upper molars and distal cusp on the lower molar, with the consequent reduction of the occlusal surface. Reduced size of occlusal surface and number cusps on upper molars resulted in the transformation of rhomboid occlusal shape into triangular, with the consequent loss of H-shaped groove system (in the upper right first molars H-shaped groove system was significantly less frequently found in TS (p < 0.05); in the upper left second molars H-shaped groove system was significantly less frequently found in TS (p < 0.01). The X-chromosome aneuploidy can cause a decrease in developmental homeostasis, which results in the alteration of apposition of the enamel and in consequently substantial changes of the molar occlusal morphological features.