Galloway-Mowat syndrome (GAMOS, OMIM: 251300) is a rare autosomal recessive (AR) neurodevelopmental disease, characterized by the combination of early-onset nephrotic syndrome and various central nervous system anomalies. The WD repeat-containing protein 73 (WDR73, OMIM: 616144) gene was the first gene found to be implicated in GAMOS1. An AR family with parental consanguinity underwent comprehensive clinical and genetic analyses. In this study, the variant identified by whole exome sequencing was confirmed by Sanger sequencing and cosegregation analysis. A literature review was conducted to summarize previously reported cases of GAMOS1 caused by mutations in the WDR73 gene. The proband with GAMOS1 was a 3-year-old boy with normal renal function and typical characteristics of GAMOS1, including idiopathic nystagmus, agenesis of genitalia, persistent axial hypotonia, mild cerebellar atrophy, thinning of the corpus callosum, and brainstem hypoplasia. A novel homozygous frameshift mutation c.972_973dupCT (p.F325Sfs * 10) in the exon 8 of the WDR73 gene was identified in the proband. We summarized thirty-six previously reported GAMOS1 cases caused by mutations in the WDR73 gene. We identified a novel homozygous frameshift mutation (c.972_973dupCT) in the WDR73 gene, causing AR GAMOS1 in a Chinese consanguineous family. The results are essential for further confirming the pathogenicity of WDR73 gene mutations and expanding the manifestation spectrum of GAMOS1.

Congenital aphallia is a rare condition with less than 100 documented cases. It may occur isolated or in association with additional anomalies such as gastrointestinal malformations, caudal defects, imperforate anus, and other genitourinary anomalies. All previously reported patients with aphallia had a normal karyotype; here, we report the first case associated with a chromosomal imbalance. A newborn was found to have an absence of the penis; a pre-sphincteric urethrorectal fistula was identified and a vesicostomy was performed. Hormonal studies at three months showed elevated levels of 17-α-hydroxyprogesterone. Physical examination at 2.5 years old revealed a bifid, rough, pigmented scrotum, without palpable gonads or a urethral meatus. Ultrasound imaging showed both testicles in the inguinoscrotal region. He also presented with some craniofacial features, including dolichocephaly, prominent forehead, left palpebral ptosis and strabismus of the right eye, convex nasal ridge, narrow and high nasal bridge, overhanging nasal tip, short philtrum, ogival palate and bifid uvula, and large low-set ears rotated posteriorly. He also had hypotonia, a broad-based gait with poor balance, moderate laxity, bilateral flat feet, umbilical hernia, corpus callosum hypoplasia, and mild intellectual disability. His karyotype was 46,XY, der(15)t(9;15)(q34;p11)dn. An aCGH analysis revealed a duplication of ~ 9.7 Mb of the 9qter region containing 246 genes: arr[GRCh37] 9q34.11q34.3(131,348,076_141,019,088)x3. To our knowledge, this is the first case of aphallia possibly associated with a chromosomal imbalance, specifically a 9q34.11-> qter duplication.

The Aristaless-related homeobox (ARX) gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of ARX-related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in ARX families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants. In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo ARX pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited variants (n=33) or variants of unknown inheritance (n=20). Altogether, the clinical spectrum of females with heterozygous pathogenic ARX variants is broad: 42.5% are asymptomatic, 16.4% have isolated agenesis of the corpus callosum (ACC) or mild symptoms (learning disabilities, autism spectrum disorder, drug-responsive epilepsy) without ID, whereas 41% present with a severe phenotype (ie, ID or developmental and epileptic encephalopathy (DEE)). The ID/DEE phenotype was significantly more prevalent in females carrying de novo variants (75%, n=15/20) versus in those carrying inherited variants (27.3%, n=9/33). ACC was observed in 66.7% (n=24/36) of females who underwent a brain MRI. By refining the clinical spectrum of females carrying ARX pathogenic variants, we show that ID is a frequent sign in females with this X linked condition.

Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis. This syndrome is caused by biallelic loss-of-function mutations in the NUP188 gene. In the physical examination of our patient, whose mother and father were third-degree relatives, hypotonia, bilateral congenital cataracts, ambiguous genitalia, hypospadias, undescended testis, and facial dysmorphic findings (hypertelorism, high palate, micrognathia, microphthalmia, low-set ears) were detected. In our patient, a homozygous c.1087C>T (p.Gln363Ter) variant was detected in exon 11 of the NUP188 (NM_015354.3) gene. The mother and father were found to be heterozygous carriers of this variant. All patients with the diagnosis of Sandestig-Stevanova syndrome reported in the literature are female. Our patient is the first male patient reported with this syndrome. In addition, immunodeficiency, congenital hypothyroidism, biotinidase deficiency, undescended testis, hypospadias, and ambiguous genitalia are defined for the first time in this syndrome. Our patient is the first case of Sandestig-Stefanova syndrome reported from Turkey. In this study, Sandestig-Stefanova syndrome with a novel pathogenic NUP188 gene variant is presented.

Disorders of sexual development can present isolated or as a part of complex genetic syndromes. A newborn with ambiguous genitalia and prenatally diagnosed brain malformations was referred to our hospital. Prenatal ultrasound examination and MRI showed lissencephaly and absence of the corpus callosum. At admission, physical examination revealed microphallus, hypospadia and complete fusion of labioscrotal folds with nonpalpable gonads, normal blood pressure and serum biochemistry. Cortisol level was normal (201 nmol/L), testosterone elevated (14.4 nmol/L), FSH 0.1 IU/L, LH 0.7 IU/L, estradiol 241 pmol/L. Seizures were noted on the 2nd day and the child was started on anticonvulsives. When 17-OHP level results came back elevated (200 nmol/L), ACTH test was performed and the child was started on hydrocortisone and fludrocortisone treatment. Congenital adrenal hyperplasia became unlikely when karyotype result showed normal male karyotype (46, XY, SRY+) with no Mullerian structures seen on ultrasonographic exam. As association of ambiguous genitalia and lissencephaly strongly suggested a mutual genetic background, diagnosis of X-linked lissencephaly with ambiguous genitalia (X-LAG) became apparent. The presented case highlights the importance of looking at the whole clinical picture instead of separate isolated findings with emphasis on patient-centered approach guided by clinical findings and patient history.