Phenotypic and molecular characterization of five patients with PIK3CA-related overgrowth spectrum (PROS).

Somatic and germline PI3K-AKT-mTOR pathway pathogenic variants are involved in several segmental overgrowth phenotypes such as the PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome, and PTEN hamartoma tumor syndrome. In this study, we describe five patients with PROS. We identified by high-throughput sequencing four different somatic PIK3CA pathogenic variants in five individuals. The Glu726Lys variant, which was previously reported in megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, was identified in two patients with unclassified PROS. The Cys420Arg substitution, which was previously reported in CLOVES, was found in a patient with fibroadipose hyperplasia. Additionally, relatively rare pathogenic variants, His1047Tyr and Tyr1021Cys, were detected in two patients with MCAP. Therefore, we suggest performing deep sequencing of PIK3CA in all patients with suspected PROS, instead of targeted polymerase chain reaction for hotspot pathogenic variants.

New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.

Sterol-C4-methyl oxidase (SC4MOL) deficiency was recently described as an autosomal recessive cholesterol biosynthesis disorder caused by mutations in the MSMO1 (sometimes also referred to as SC4MOL) gene. To date, 5 patients from 4 unrelated families with SC4MOL deficiency have been reported. Diagnosis can be challenging as the biochemical accumulation of methylsterols can affect global development and cause skin and ocular pathology. Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay. We undertook whole-exome sequencing and identified a new homozygous missense mutation c.81A>C; p.Asn27Thr in MSMO1. Segregation analysis in all available family members confirmed recessive inheritance of the mutation. The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement. This study demonstrates how genomics-based diagnosis and therapy can be helpful in clinical practice.

Cytogenetic, Molecular, and Phenotypic Characterization of a Patient with de novo Derivative Chromosome 18 and Review of the Literature.

We present a patient with a de novo derivative chromosome 18 which includes a terminal deletion of 18p and a terminal duplication of 18q accompanied by a cryptic duplication of 18p. The girl had mild dysmorphic features such as micro-retrognathia, upslanted palpebral fissures, bilateral epicanthus, high palate, low-set ears, short neck, and full cheeks. She also had an H-type tracheoesophageal fistula which required surgery. Her cognitive and motor skills were delayed. Karyotype analysis showed an additional segment on the short arm of chromosome 18. Chromosomal microarray revealed a 7.3-Mb terminal loss from 18p11.32 to 18p11.23, a 22.2-Mb terminal gain from 18q21.31 to 18q23, and a 3.9-Mb interstitial gain from 18p11.22 to 18p11.21. We hypothesize that the mother has gonadal mosaicism for normal chromosome 18, der(18)dup(p11.22p11.21), and der(18)dup(p11. 22p11.21)inv(18)(p11.22q21.31), or both the terminal del/dup and the interstitial duplication occurred simultaneously.

A novel variant of the STAR gene: nonclassical presentation from Turkey.

OBJECTIVES: Lipoid congenital adrenal hyperplasia (LCAH) is a rare autosomal recessive disease caused by mutations in the steroidogenic acute regulatory protein (STAR) gene, expressed in the adrenal and gonadal tissues. In classical LCAH, individuals with 46, XY chromosomes present with a female appearance of the external genitalia due to insufficient androgen production. In the non-classical form, a milder phenotype is observed with male external genitalia. Here, we present a non-classical LCAH diagnosis with a newly identified c.266T>A (p.Ile89Asn) likely pathogenic homozygous variant in a 46, XY infant. CASE PRESENTATION: A three-month-and-thirteen-day-old male proband presented with clinical features of cortisol and mineralocorticoid deficiencies. The manifestation of salt-wasting syndrome occurred relatively late, and although the external genitalia appeared male, there was a mild virilization defect. The combination of mild impairment in androgen production and severe salt-wasting syndrome is an intriguing finding in our patient. Peripheral blood samples were obtained from the patient and his family. The newly identified variant, determined by next-generation sequencing analysis, was confirmed by segregation analysis showing carrier status in both parents. CONCLUSIONS: We aim to contribute to the literature by elucidating molecular mechanisms by presenting an atypical presentation and a newly identified variant.

A Novel RNPC3 Gene Variant Expands the Phenotype in Patients with Congenital Hypopituitarism and Neuropathy.

INTRODUCTION: Pathogenic biallelic RNPC3 variants cause congenital hypopituitarism (CH) with congenital cataracts, neuropathy, developmental delay/intellectual disability, primary ovarian insufficiency, and pituitary hypoplasia. Here, we aimed to evaluate the clinical and molecular characteristics of 2 patients with CH and neuropathy. MATERIALS AND METHODS: Proband was evaluated by clinical, laboratory, and radiological exams, followed by exome sequencing (ES). Clinical investigation of an affected sibling and variant segregation in the family was performed by Sanger sequencing. A three-dimensional protein model study was conducted to predict the effect of the variant on the function of the RNPC3 peptide. RESULTS: Proband was a 16-month-old girl who was referred for the evaluation of failure to thrive. Her height, weight, and head circumference were 55.8 cm (-7.6 SDS), 6.5 kg (-3.6 SDS), and 41.8 cm (-3.82), respectively. She had a developmental delay and intellectual disability. Central hypothyroidism, growth hormone, and prolactin deficiencies were identified, and MRI revealed pituitary hypoplasia. Electroneuromyography performed for the gait abnormality revealed peripheral neuropathy. A homozygous novel variant c.484C>T/p.(Pro162Ser) in the RNPC3 was detected in the ES. Her brother had the same genotype, and he similarly had pituitary hormone deficiencies with polyneuropathy. CONCLUSION: Expanding our knowledge of the spectrum of RNPC3 variants, and apprehending clinical and molecular data of additional cases, is decisive for accurate diagnosis and genetic counseling.

Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome.

OBJECTIVE: Joubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement. METHODS: We retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes. RESULTS: The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber's congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene. CONCLUSION: Some rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.

Promising effect of intravenous immunoglobulin therapy for epidermolysis bullosa pruriginosa.

BACKGROUND: Epidermolysis bullosa pruriginosa (EBP) is rare a clinical variant of dystrophic epidermolysis bullosa characterized by trauma-induced bullae formation, milia and nail dystrophy accompanied by severe pruritus. Treatment pruritus of EBP focuses on immunosuppressive treatment with limited efficacy. Treatment strategies are not well-established. AIM: To provide the genetic characterization of a multi-generational EBP family and discuss the efficacy of intravenous immunoglobulin treatment in EBP. MATERIALS & METHODS: The clinical characteristics of patients diagnosed with EBP in three consecutive generations were determined. The mutation is analyzed in the index patient's genomic DNA by Sanger sequencing, and this mutation was confirmed in other affected members of the family. Index case with severe phenotype was treated with intravenous immunoglobulin (IVIG). RESULTS: A heterozygous single nucleotide transition, c.6127G>A, in exon 73 of COL7A1 was identified in all affected members. Physical examination of patients revealed lichenoid papules on extensor surfaces of extremities, excoriations, milia formation and nail dystrophy. Majority of patients had elevated serum IgE levels (%86 (6/7)) without a medical history for atopy. Female patients had generalized involvement and severe phenotype. The skin lesions of the index case were refractory to high dose systemic steroids and cyclosporine treatment. Lesions improved significantly with intravenous immunoglobulin therapy. CONCLUSION: In severe cases, unresponsive to other therapies, IVIG may be a preferable therapeutic approach to modulate the inflammatory response in patients with EBP.