Central Diabetes Insipidus Caused by Arginine Vasopressin Gene Mutation: Report of a Novel Mutation and Review of Literature.

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant hereditary disorder characterized by severe polydipsia and polyuria that usually presents in early childhood. In this study, we describe a new arginine vasopressin (AVP) gene mutation in an ethnic German family with FNDI and provide an overview of disease-associated AVP-gene mutations that are already described in literature. Three members of a German family with neurohypophyseal diabetes insipidus were studied. Isolated DNA from peripheral blood samples was used for mutation analysis by sequencing the whole coding region of AVP-NPII gene. Furthermore, we searched the electronic databases MEDLINE (Pubmed) as well as HGMD, LOVD-ClinVar, db-SNP and genomAD in order to compare our cases to that of other patients with FNDI. Genetic analysis of the patients revealed a novel heterozygote missense mutation in exon 2 of the AVP gene (c.274T>G), which has not yet been described in literature. We identified reports of more than 90 disease-associated mutations in the AVP gene in literature. The novel mutation of the AVP gene seems to cause FNDI in the presented German family. Similar to our newly detected mutation, most mutations causing FNDI are found in exon 2 of the AVP gene coding for neurophysin II. Clinically, it is important to think of FNDI in young children presenting with polydipsia and polyuria.

Cushing's disease in a patient with steroid 21-hydroxylase deficiency.

Cushing's disease rarely appears as a consequence of hereditary disease. However, familial diseases with diminished glucocorticoid feedback are associated with secondary hypercorticotropinism and have been shown to give rise to pituitary adenomas. We here describe the rare case of a 30-year old female patient with congenital adrenal hyperplasia who also showed clinical signs and a typical history of hypercortisolism that was specified as Cushing's disease. After removal of a pituitary microadenoma, serum-cortisol levels fell below normal and the symptoms improved. However, after four years the menstrual cycle was irregular again and ACTH levels were in the upper range of normal. A corticotropin challenge showed a minor cortisol response but a marked increase in 17-hydroxyprogesterone serum concentrations. Genetic analysis revealed a homozygous mutation in exon 7 of the CYP21A2 gene (CTG>TTG, p.V281L). We conclude that a marked ACTH drive was able to override insufficient 21-hydroxylation and even to cause hypercortisolism. Although we describe a rare case, the impairment of the glucocorticoid feedback system in the context of congenital adrenal hyperplasia and other diseases may contribute to the development of secondary hypercorticotropinism as well as corticotropin producing adenomas.

Analysis of rare APC variants at the mRNA level: six pathogenic mutations and literature review.

In monogenic disorders, the functional evaluation of rare, unclassified variants helps to assess their pathogenic relevance and can improve differential diagnosis and predictive testing. We characterized six rare APC variants in patients with familial adenomatous polyposis at the mRNA level. APC variants c.531 + 5G>C and c.532-8G>A in intron 4, c.1409-2_1409delAGG in intron 10, c.1548G>A in exon 11, and a large duplication of exons 10 and 11 result in a premature stop codon attributable to aberrant transcripts whereas the variant c.1742A>G leads to the in-frame deletion of exon 13 and results in the removal of a functional motif. Mutation c.1548G>A was detected in the index patient but not in his affected father, suggesting mutational mosaicism. A literature review shows that most of the rare APC variants detected by routine diagnostics and further analyzed at the transcript level were evaluated as pathogenic. The majority of rare APC variants, particularly those located close to exon-intron boundaries, could be classified as pathogenic because of aberrant splicing. Our study shows that the characterization of rare variants at the mRNA level is crucial for the evaluation of pathogenicity and underlying mutational mechanisms, and could lead to better treatment modalities.

Czech dysplasia: report of a large family and further delineation of the phenotype.

Czech dysplasia (OMIM 609162) is a recently delineated COL2A1 disorder characterized by early-onset progressive pseudorheumatoid arthritis, platyspondyly, short third and fourth metatarsals, normal height, and the absence of ophthalmological problems or cleft palate. Czech dysplasia is caused by a specific missense mutation (R275C, c.823C > T) in the triple helical domain of the COL2A1 gene. We report on a large family with 11 patients with typical Czech dysplasia and sensorineural hearing loss. Hearing loss has hitherto not been considered as a major manifestation of Czech dysplasia. Mutation analysis documented the COL2A1 c.823C > T (R275C) mutation in all affected individuals. Thus, Czech dysplasia is possibly caused exclusively by the R275C mutation, which is a unique situation among the COL2A1 disorders. The family provides further evidence for the remarkably uniform manifestation of the clinical and radiological abnormalities and adds hearing loss to the list of major anomalies of Czech dysplasia.

A novel stop mutation (p.(Gln22*)) of DAX1 (NR0B1) results in late-onset X-linked adrenal hypoplasia congenita.

DAX1 (NR0B1) is an orphan nuclear receptor, which plays an important role in development and function of the adrenal glands and gonads. Mutations in DAX1 cause X-linked adrenal hypoplasia congenita (X-linked AHC), which is characterized by adrenal insufficiency (AI) and hypogonadotropic hypogonadism (HHG). Affected boys present with adrenal failure usually in childhood and, later in life, with delayed puberty. However, patients with a late-onset form of X-linked AHC have also been described in the past years. We report a male patient who presented with symptoms of an adrenal crisis at the age of 38 years and was later diagnosed with HHG. Family history was positive with several male relatives diagnosed with AI and compatible with the assumed X-chromosomal inheritance of the trait. Direct sequencing of DAX1 of the patient revealed a hemizygous cytosine-to-thymine substitution at nucleotide 64 in exon 1, which creates a novel nonsense mutation (p.(Gln22*)). In order to compare the clinical presentation of the patient to that of other patients with X-linked AHC, we searched the electronic database MEDLINE (PubMed) and found reports of nine other cases with delayed onset of X-linked AHC. In certain cases, genotype-phenotype correlation could be assumed. LEARNING POINTS: X-linked AHC is a rare disease characterized by primary AI and hypogonadotropic hypogonadism (HHG). The full-blown clinical picture is seen usually only in males with a typical onset in childhood.Patients with a late-onset form of X-linked AHC have also been described recently. Being aware of this late-onset form might help to reach an early diagnosis and prevent life-threatening adrenal crises.Adult men with primary AI of unknown etiology should be investigated for HHG. Detecting a DAX1 mutation may confirm the clinical diagnosis of late-onset X-linked AHC.In relatives of patients with genetically confirmed X-linked AHC, targeted mutation analysis may help to identify family members at risk and asymptomatic carriers, and discuss conscious family planning.

A patient with novel mutations causing MEN1 and hereditary multiple osteochondroma.

UNLABELLED: We report of a male patient aged 32 years who presented with primary hyperparathyroidism. Three parathyroid glands were resected. At the age of 46 years, nervus facialis irritation was noted, and an MRI scan incidentally revealed a non-functioning pituitary adenoma with affection of the chiasma opticum. The patient underwent transsphenoidal operation resulting in pituitary insufficiency postoperatively. At the same time, primary hyperparathyroidism reoccurred and a parathyroid adenoma located at the thymus was resected. The mother of the patient died early due to multiple tumors. The patient was suspected to have multiple endocrine neoplasia type 1 (MEN1) and genetic analysis was performed. In addition, on clinical examination, multiple exostoses were noticed and an additional genetic analysis was performed. His father was reported to have multiple osteochondromas too. MEN1 was diagnosed in the patient showing a novel heterozygote mutation c.2T>A in exon 2, codon 1 (start codon ATG>AAG;p.Met1?) of the MEN1 gene. In genetic mutational analysis of the EXT1 gene, another not yet known mutation c.1418-2A>C was found in intron 5 of the EXT1 gene (heterozygotic). In conclusion, we report novel mutations of the EXT1 and the MEN1 genes causing hereditary multiple osteochondromas and MEN1 in one patient. LEARNING POINTS: It is important to ask for the patient's family history in detail.Patients with MEN1 are characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues, most frequently parathyroid (95%), enteropancreatic neuroendocrine (50%), and anterior pituitary (40%) tissues.Familiar MEN1 has a high degree of penetrance (80-95%) by the age over 50; however, combinations of the tumors may be different in members of the same family.Patients with EXT1 gene mutations should be monitored for possible transformation of bone lesions into osteochondrosarcoma.

Next generation sequencing as a useful tool in the diagnostics of mosaicism in Alport syndrome.

Alport syndrome (ATS) is a progressive hereditary nephropathy characterized by hematuria and/or proteinuria with structural defects of the glomerular basement membrane. It can be associated with extrarenal manifestations (high-tone sensorineural hearing loss and ocular abnormalities). Somatic mutations in COL4A5 (X-linked), COL4A3 and COL4A4 genes (both autosomal recessive and autosomal dominant) cause Alport syndrome. Somatic mosaicism in Alport patients is very rare. The reason for this may be due to the difficulty of detection. We report the case of a boy and his mother who presented with Alport syndrome. Mutational analysis showed the novel hemizygote pathogenic mutation c.2396-1G>A (IVS29-1G>A) at the splice acceptor site of the intron 29 exon 30 boundary of the COL4A5 gene in the boy. The mutation in the mother would not have been detected by Sanger sequencing without the knowledge of the mutational analysis result of her son. Further investigation of the mother using next generation sequencing showed somatic mosaicism and implied potential germ cell mosaicism. The mutation in the mother has most likely occurred during early embryogenesis. Analysis of tissue of different embryonic origin in the mother confirmed mosaicism in both mesoderm and ectoderm. Low grade mosaicism is very difficult to detect by Sanger sequencing. Next generation sequencing is increasingly used in the diagnostics and might improve the detection of mosaicism. In the case of definite clinical symptoms of ATS and missing detection of a mutation by Sanger sequencing, mutational analysis should be performed by next generation sequencing.

Mosaic and complete tetraploidy in live-born infants: two new patients and review of the literature.

Tetraploidy is a very rare finding in live-born infants. Nine infants with tetraploidy have been reported earlier. The phenotype is of variable severity and consists of prenatal and/or postnatal growth retardation, developmental delay, mental retardation, dysmorphic features, and skeletal and internal abnormalities. Here we present a girl aged 2 years and 7 months with a mosaic tetraploidy detected in lymphocytes, and a newborn boy with a complete tetraploidy, who died 30 h after birth. They both show growth retardation, microcephaly, developmental delay, and craniofacial dysmorphisms. The clinical features of 22 patients reported earlier are reviewed.

Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11{beta}-hydroxylase deficiency.

CONTEXT: Steroid 11beta-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency. OBJECTIVE: The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254_A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations. METHODS: We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein. RESULTS: All mutations (p.W116G, p.A165D, p.K254_A259del) found in patients with classic 11OHD have absent or very little 11beta-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively. CONCLUSION: Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling in 11OHD.