A rare case of skeletal dysplasia: biallelic variant in ACAN gene.

OBJECTIVES: Spondylo-epimetaphyseal dysplasia-aggregan (SEMD-ACAN) is a rare form of osteo-chondrodysplasia that includes vertebral, epiphyseal and metaphyseal dysplasia. It occurs as a result of loss-of-function mutations in the ACAN gene, which encodes aggregan protein, which is the basic component of the extracellular matrix in cartilage. It results in disproportionately short stature and skeletal abnormalities. Here, we aimed to present the fourth SEMD-ACAN report in the literature. CASE PRESENTATION: A 9-year-old girl was admitted to our clinic with growth retardation. She was born from a first-degree cousin marriage with severe short stature (41 cm; -3.54 SDS). Her mother also had severe short stature. Her height was 110 cm (-4.6 SDS); she had midface hypoplasia, low-set ears, short neck, short limbs, and central obesity. Biochemical and hormonal tests were normal. Skeletal survey showed moderate platyspondylia, thoracolumbar scoliosis, lumbar lordosis, bilateral femoro-acetabular narrowing, and advanced bone age (10 years). The patient's brother was 100 cm (-3.97 SDS). He had similar but milder clinical findings. Biallelic ACAN variation (c.512C>T; p. Ala171Val) was detected in two siblings by next-generation sequencing. The parents were heterozygous carriers. Before, the heterozygous form of this variant has been reported in a 15-year-old boy with short stature, advanced bone age, and dysmorphic features. CONCLUSIONS: SEMD-ACAN is a rare genetic condition that affects bone growth and development and can cause physical and developmental abnormalities. This article highlights the importance of considering genetic testing in characteristic symptoms associated with SEMD-ACAN, such as severe growth retardation and skeletal abnormalities.

Identification of a novel homozygous NR5A1 variant in a patient with a 46,XY disorders of sex development.

OBJECTIVES: Nuclear receptor subfamily 5 group A member 1 (NR5A1) is a transcription factor critical for the development of various organs. Pathogenic variants in NR5A1 are associated with a spectrum of disorders of sex development (DSD). CASE PRESENTATION: A 15-month-old baby, raised as a girl, was referred for genital swelling and ambiguous genitalia. Born to healthy consanguineous parents, the baby had a phallus, perineal hypospadias, labial fusion, and a hypoplastic scrotum. Hormonal evaluation showed normal levels, and ultrasonography revealed small gonads and absence of Müllerian derivatives. Post-human chorionic gonadotropin (hCG) testing indicated an adequate testosterone response. The karyotype was 46,XY, and in it was found a homozygous NR5A1 variant (c.307 C>T, p.Arg103Trp) in a custom 46 XY DSD gene panel. Notably, the patient exhibited complete sex reversal, hyposplenia, and no adrenal insufficiency. CONCLUSIONS: Previously, NR5A1 pathogenic variants were considered to be dominantly inherited, and homozygous cases were thought to be associated with adrenal insufficiency. Despite the homozygous pathogenic variant, our patient showed hyposplenism with normal adrenal function; this highlights the complexity of NR5A1 genotype-phenotype correlations. These patients should be monitored for adrenal insufficiency and DSD as well as splenic function.

Clinical and Genetic Characteristics of Patients with Common and Rare Types of Congenital Adrenal Hyperplasia: Novel Variants in STAR and CYP17A1.

Objectives: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases characterized by salt wasting or virilization. 21 hydroxylase deficiency (21-OHD) accounts for 90-95% of all cases of CAH and caused by the genetic defects of CYP21A2. Other forms include 3-ß-hydroxysteroid dehydrogenase deficiency, 11-ß-hydroxylase deficiency (11ß-OHD) (%5-8), 17-α-hydroxylase deficiency (17α-OHD), and steroidogenic acute regulatory protein (STAR) defects (congenital lipoid adrenal hyperplasia) with mutations in HSD3B2, CYP11B1, CYP17A1, and STAR, respectively. Objectives: Herein, we aimed to present the clinical and genetic features of 64 patients with various types of CAH. Methods: Sixty-four patients with CAH, monitored in the Izmir Dr. Behcet Uz Children Hospital Division of Pediatric Endocrinology, were retrospectively analyzed for the clinical, laboratory, and genetic data. Results: Fifty-six patients (87.5%) had 21-OHD and four patients (6.3%) had 17α-OHD, three patients (4.7%) had 11ß-OHD, and one patient (1.5%) had STAR defect. The most common presenting features in 21-OHD were ambiguous genitalia. Patients with 21-OHD were diagnosed earlier than the rare groups. Disease-causing variants of CYP21A2 were identified in 46 patients. The most common mutations were IVS2, Q318X, I172N, and large deletions. Three patients with 11ß-OHD were presented with enlargement of penis and early pubic hair at the median presenting age of 26 months. 17α-OHD deficiency was detected in 4 cases. Genetic analysis revealed two different homozygous CYP17A1 variants. The patient with STAR defect was presented with dehydration and cholestasis in 44 days of the life. Genetic analysis of patient with STAR deficiency revealed a novel homozygous variant. Conclusion: The current study reported a genotype-phenotype correlation consistent with literature data in CAH cases with 21-OHD. This study also reported novel homozygous variants in STAR and CYP17A1 genes that lead to rare types of CAH.

A novel synonymous homozygous variant [c.2538G>A (p.Thr846Thr)] in TRPM6 in a patient with hypomagnesemia with secondary hypocalcemia.

OBJECTIVES: Hypomagnesemia 1, intestinal (HOMG1) is characterized by neurological symptoms that occur due to hypocalcemia and hypomagnesemia and caused by mutations in the TRPM6. Most of the identified variants in TRPM6 lead to premature termination: nonsense, frameshift, deletion, and splice site mutations. CASE PRESENTATION: Herein, we report a 1.5 month-old case who presented with convulsion due to hypocalcemia and hypomagnesemia in the early infancy. Sequencing of TRPM6 revealed a novel homozygous synonymous variant [c.2538G > A (p.Thr846Thr)] in the last codon of exon 19, which is most likely to affect the splicing. We report a novel homozygous synonymous variant in the TRPM6 leading to HOMG1, expanding the mutational spectrum. CONCLUSIONS: Synonymous mutations that were previously considered as harmless should be evaluated at the nucleotide level, keeping in mind that they may affect splicing and cause to the disease.

Investigating the Efficiency of Vitamin D Administration with Buccal Spray in the Treatment of Vitamin D Deficiency in Children and Adolescents

Objective: The aim of this study was to evaluate the efficiency of a buccal spray form of vitamin D compared to single oral dose (stoss therapy) and oral drops therapy in the treatment of vitamin D deficiency. Methods: Ninety healthy children and adolescents (3-18 years) with vitamin D deficiency [serum level of 25-hydroxyvitamin D (25(OH) D) <12 ng/mL] were randomized to receive vitamin D3 buccal spray (2000 U, n=30, group 1) for six weeks, oral drops (2000 U, n=30, group 2) for six weeks and a single oral dose (300 000 U) vitamin D3 (n=30, group 3). Serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone and 25(OH)D levels of the patients were measured at baseline and after the treatment on the 42nd day. Results: All three groups had a significant increase in serum 25(OH)D concentrations (p<0.001). In group 1, baseline mean 25(OH)D was 8.0±0.41 ng/mL, which rose to 22.1 (17.8-28.2) ng/mL after treatment with a mean increase of 15.6±1.3 ng/mL. Similarly in group 2, baseline, post-treatment and mean increase in 25(OH)D concentrations were 7.9±0.45 ng/mL, 24.4 (20.6-29.6) ng/mL and 17.3±1.1 ng/mL while for group 3 these values were 7.6±0.47 ng/mL, 40.3 (29.4-58.4) ng/mL and 34.3±3.2 ng/mL, respectively. Conclusion: We conclude that vitamin D3 supplementation with buccal spray and oral drops is equally effective in terms of raising vitamin D concentrations in short-term treatment of vitamin D deficiency.

Identification of two AMH gene variants in two unrelated patients with persistent Müllerian duct syndrome: one novel variant.

INTRODUCTION: Persistent müllerian duct syndrome (PMDS) is a rare form of 46, XY disorder of sex development characterized by the persistence of the müllerian structures (uterus, fallopian tubes, the upper part of the vagina) in phenotypically and genotypically normal males. This disease occurs as a result of impairment in the synthesis, release or effect of anti-Müllerian hormone (AMH) during the embryonic period. Approximately 85-88% of PMDS cases have been reported to have AMH or AMHRII mutation. CASE: Herein, we report two PMDS cases from unrelated two families who presented with bilateral undescended testes, persistence of müllerian remnants, and low/undetectable serum AMH levels. Molecular genetic analysis revealed two homozygous variants in AMH. The first one is a novel missense variant (c.1315C > T), the latter is a frameshift variant caused by a deletion (c.343_344delCT), which is less frequently reported type in AMH. CONCLUSION: The diagnosis of PMDS should be kept in mind in patients with externally normal males, bilateral cryptorchidism, and signs of müllerian remnants on laparoscopy.

Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations.

CONTEXT: Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. OBJECTIVE: To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. SETTING: Twelve tertiary pediatric endocrine referral centers. PATIENTS: Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. MAIN OUTCOME MEASURES: Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. RESULTS: Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = -3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: -2.35, median BMI SDS: -0.52 SDS) with 20/29 (69%) cases having growth retardation. CONCLUSION: We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

Three Siblings with Idiopathic Hypogonadotropic Hypogonadism in a Nonconsanguineous Family: A Novel KISS1R/GPR54 Loss-of-Function Mutation

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disease caused by defects in the secretion of gonadotropin releasing hormone (GnRH) or the action of GnRH on the pituitary gonadotrophes. KISS1R is one of the genes which, when mutated, cause IHH and mutations of this gene are responsible for about 2-5% of patients with normosmic IHH (NIHH). In this report, we present three siblings with NIHH due to a compound heterozygous KISS1R mutation. Genetic studies were carried out in the 14 year old index case with IHH and three siblings, two of whom were prepubertal. Genomic DNA was extracted from peripheral leukocytes and KISS1R gene was sequenced by using standard polymerase chain reaction amplification procedures. In molecular analysis of the index case, a compound heterozygous mutation was determined in KISS1R gene c.969C>A (p.Y323X) (known pathogenic) and c.170T>C (p.L57P) (novel). Mutation c.170T>C (p.L57P) was inherited from the mother while c.969C>A (p.Y323X) was inherited from the father. The same genotype was also found in two of the three siblings. A compound heterozygous mutation of the KISS1 gene, including one novel mutation, was found to cause NIHH and also incomplete puberty in a non-consanguineous family.