Autism spectrum disorder in a patient with Nicolaides-Baraitser Syndrome: case report.

Nicolaides-Baraitser Syndrome is a rare genetic condition that clinically presents with intellectual disabilities, facial and bone changes, and sparse hair. In Brazil, only one case has been previously reported without genetic confirmation. We present the case of an 8-year-old boy, clinically and genetically diagnosed with Nicolaides-Baraitser Syndrome, who developed autism spectrum disorder characteristics with a formal diagnosis at the age of eight. Diagnosing autism spectrum disorder in patients with intellectual disabilities is a clinical challenge requiring careful evaluation.

Non-syndromic hypotrichosis: A report of two novel variants in the LSS gene.

To date, more than 15 genes have been linked to syndromic and non-syndromic hypotrichosis, among which the LSS gene encoding lanosterol synthase was recently linked to autosomal recessive isolated hypotrichosis. Here we report the case of a 6-year-old girl born to non-consanguineous Iraqi parents and presenting with sparse lanugo hair since birth on the scalp, eyelashes, and eyebrows. Whole exome sequencing followed by Sanger sequencing allowed the detection of two novel compound heterozygous variants in LSS (p.Ile323Thr and p.Gly600Val). Reporting and investigating further cases with LSS variants might help establishing a better genotype-phenotype correlation.

Identification of a novel sporadic U2HR pathogenic variant in a patient with Marie Unna hereditary hypotrichosis.

Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant hair loss disorder characterized by coarse, wiry, and twisted hair developing during early childhood, and followed by progressive hair loss with puberty. We report a sporadic case of a 4-year-old boy with clinical features suggestive of MUHH, in whom we identified the new pathogenic variant c.67C>T; p.(Gln23*) in U2HR. This finding extends the known spectrum of U2HR variants underlying MUHH and increases genetic information for further genotype-phenotype correlation.

Hypotrichosis with Juvenile Macular Dystrophy in a Patient with Cadherin 3 (CDH3) Mutation.

INTRODUCTION: Hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal recessive disease with progressive macular degeneration leading to blindness in the first three decades of life along with hypotrichosis. CASE: We herein report a case of a five year old boy with hypotrichosis with juvenile macular dystrophy diagnosed with multi-modal imaging which was later confirmed by genetic testing by whole genome sequencing. OBSERVATIONS: Fundus examination of both eyes revealed symmetrical hypopigmentation in peripapillary retinal pigment epithelium (RPE) involving posterior pole and surrounded by a mottled hyperpigmented border. Fundus autofluorescence showed central hypo autofluorescence with surrounding hyper autofluorescence corresponding to RPE atrophy and a faint hypo autofluorescence at the junction of normal retina. SD-OCT showed segmental outer retinal and choriocapillaris atrophy temporal to fovea with interdigitation zone and ellipsoid zone loss and RPE irregularities with hyperreflective subretinal deposits at the fovea. Electroretinogram showed normal waves but a slight reduction of b wave amplitude in both eyes. He had sparse scalp-hair. CONCLUSION: Children with reduced vision not falling into a typical macular degeneration should be examined systemically and may just have sparse scalp hair and still have a genetic disease. A regular follow-up should be emphasized in view of progressive nature of the disease.

Botanical extracts in combination improve autosomal recessive woolly hair/hypotrichosis caused by LIPH mutations.

BACKGROUND: Mutation in the lipase H (LIPH) gene is a main reason for autosomal recessive woolly hair (ARWH)/hypotrichosis. Although some studies reported that topical minoxidil could improve ARWH, an effective treatment method for this disease is still lacking. AIM: We attempt to explore potential treatment options for ARWH. MATERIALS & METHODS: A female 6-year-old child was diagnosed with ARWH/hypotrichosis caused by LIPH mutations. And she was treated with combined treatment of botanical extracts. RESULTS: After 6 months of treatment, the patient's hair grew remarkably. After 4 years of treatment, the patient's hair remained dense. DISCUSSION: After the combination treatment, the patient saw a favorable clinical effect. However, the specific mechanisms of action for botanical extracts require further validation. In addition, some regenerative strategies may be considered as potential treatment options for ARWH. We should actively attempt treatment for ARWH patients and encourage prenatal diagnosis due to the great impact of hair loss. CONCLUSION: The combined therapy of botanical extracts may improve ARWH long-term with a sustainable therapeutic effect.

The first reported case of CDH3-related hypotrichosis with juvenile macular dystrophy from Jordan: a case report.

BACKGROUND: Pathogenic variants in the Cadherin 3 (CDH3) gene are responsible for the occurrence of Hypotrichosis with Juvenile Macular Dystrophy (HJMD) and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy Syndrome (EEMS), both of which are rare autosomal recessive disorders characterized by hypotrichosis and progressive macular dystrophy. The CDH3 gene encodes for P-cadherin, a calcium-binding protein that is essential for cell-cell adhesion, which is expressed in the retinal pigment epithelial cells and hair follicles. MATERIALS AND METHODS: Fundus examination of both eyes was done in addition to clinical investigation. Genomic DNA was extracted from a whole-blood sample and whole-exome sequencing (WES) was performed to identify the underlying etiology.All identified variants were evaluated for their pathogenicity and causality. RESULTS: We present the first case of HJMD in a 23-year-old female patient from Jordan. The patient presented to our ophthalmology clinic with poor vision in both eyes. Gross examination revealed sparse scalp hair along with macular dystrophy on fundus exam in both eyes. HJMD was suspected and whole-exome sequencing (WES) confirmed the diagnosis with the identification of a homozygous frameshift deletion (p.Gly277AlafsTer20) localised in exon 7 of the CDH3 gene. CONCLUSION: Blindness due to progressive macular degeneration is a common manifestation in numerous syndromic recessive disorders such as HJMD. Ophthalmologists should consider the importance of systemic manifestations and genetic testing for the confirmation of diagnosis.

The first Japanese family of CDH3-related hypotrichosis with juvenile macular dystrophy.

BACKGROUND: Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive inherited disorder caused by biallelic variants in the CDH3 gene encoding P-cadherin. Here, we report two Japanese sibling patients with HJMD. METHODS: Whole-exome sequencing (WES) was performed to identify disease-causing variants. In addition, ophthalmic and dermatological examinations were performed to classify the phenotype of each patient. RESULTS: The WES analysis revealed novel compound heterozygous CDH3 variants [c.123_129dupAGGCGCG (p.Glu44fsX26) and c.2280+1G>T] in both patients; the unaffected, nonconsanguineous parents each exhibited one of the variants. Both patients showed the same clinical findings. Ophthalmologically, they exhibited progressive loss of visual acuity and chorioretinal macular atrophy, as examined with fundoscopy, fundus autofluorescence imaging, and optical coherence tomography. Full-field electroretinography, assessing generalized retinal function, revealed nearly normal amplitudes of both rod- and cone-mediated responses. Multifocal electroretinography, reflecting macular function, showed extremely decreased responses in the central area, corresponding to the chorioretinal atrophy. Dermatological examination revealed diffuse thinning of the scalp hair, which was sparse and fragile. CONCLUSION: This is the first report of Japanese patients with HJMD and novel compound heterozygous truncating variants in CDH3. Our findings can expand the knowledge and understanding of CDH3-related HJMD, which could be helpful to ophthalmologists and dermatologists.

Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects.

Nicolaides-Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via "Network Therapy of Rare Epilepsies (NETRE)" and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy.

Novel mutations in Chinese hypotrichosis simplex patients associated with LSS gene.

Hypotrichosis simplex (HS) is a rare form of hereditary alopecia caused by a variety of genetic mutations. Currently, only four studies regarding LSS-related HS have been reported. In this study, we try to make a definite diagnosis in two unrelated Chinese families with three pediatric patients clinically suspected of HS. Whole-exome sequencing (WES) was performed for these two families to reveal the pathogenic mutation. WES revealed two different compound heterozygous mutations in LSS in two probands that confirmed the diagnosis, including three novel mutations. In this paper, we describe a new accompanying phenotype of teeth dysplasia in a HS patient. Moreover, we provide a review of all reported LSS mutation-related patients and infer some potential genotype-phenotype correlations for the first time.