Neurogenic bladder and neuroendocrine abnormalities in Pol III-related leukodystrophy.

BACKGROUND: Pol III-related leukodystrophies, including 4H leukodystrophy, are recently recognized disorders that comprise hypomyelination and various neurologic and non-neurologic clinical manifestations. We report the unique neurologic presentation of the micturition dysfunction in Pol III-related leukodystrophy and describe the novel endocrine abnormalities in this entity. CASE PRESENTATION: A 32-year-old Caucasian female exhibited chronic urinary incontinence that commenced at the age of 7 years and remained the unexplained symptom more than two decades before the onset of progressive neurologic decline. A transient growth failure and absent sexual development with hypoprolactinemia appeared in the meanwhile. Neurologic, endocrine, neuroradiologic, and genetic evaluation performed only in the patient's thirties, confirmed the diagnosis of 4H leukodystrophy as the only cause of the micturition disturbance. CONCLUSION: The report shows for the first time that an unexplained chronic bladder dysfunction should be evaluated also as a possible 4H leukodystrophy, thus alerting to the unexpected neurologic and endocrine features in 4H leukodystrophy.

Börjeson-Forssman-Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.

Salivary testosterone for the diagnosis of androgen deficiency in end-stage renal disease.

BACKGROUND: Hypogonadism is frequent in patients with end-stage renal disease (ESRD). Salivary testosterone (Sal-T) is a non-invasive tool to screen androgen deficiency in adult male with normal renal function. However, available data on its utility in ESRD are not conclusive. OBJECTIVES: The objectives of the study were: (i) to compare free testosterone fractions in saliva (SAL-T) and serum (Free-T); (ii) to establish the correlation of Sal-T with circulating total (TT) and bioavailable testosterone (Bio-T); (iii) to detect androgen deficiency through Sal-T; (iv) to determine the correlation of Sal-T with clinical parameters. METHODS: The study included: 60 adult ESRD men on haemodialysis (20-60 years old) with decreased libido referred from two dialysis centres; 112 eugonadic and 40 hypogonadic adult men with normal renal function as controls. Simultaneous morning saliva and serum samples were obtained for testosterone measurements by liquid RIA (SAL-T; TT). Free-T and Bio-T were calculated by the Vermeulen equation. RESULTS: Sal-T (0.338±0.177 nM) and Free-T (0.338±0.165 nM) did not differ (P>0.900) in ESRD as well as in control (0.337±0.182 and 0.337±0.172 nM, respectively; P>0.900). Sal-T levels correlated positively (P<0.0001) with Free-T (r=0.95), TT (r=0.80) and Bio-T (r=0.76) in ESRD. Sal-T negatively correlated with age and years on dialytic therapy. Sal-T showed 100% sensitivity and specificity to differentiate patients with androgen deficiency (22%) from those with normal androgen levels (78%). Hypogonadism was hypergonadotrophic in 69% cases and hypogonadotrophic in 31%. CONCLUSIONS: These data demonstrate the value of morning Sal-T testing as a non-invasive approach to screen androgen status in ESRD patients.

Effects of aging, gender, and hypogonadism on mandibular bone density.

AIM: The aim of the present study was to evaluate how aging, sex, and hypogonadism influence mandibular bone density with and without the benefits of hormone treatment. METHODS: Three-month old Wistar rats were randomly assigned to three experimental groups, with eights animals per group: controls, castrated (orchiectomized [ORX], ovariectomized [OVX]) and castrated with hormonal treatment (ORX + testosterone, OVX + estradiol benzoate). Females were previously evaluated by vaginal cytology. The corporal mass was verified weekly, and after three experimental periods (90, 120, and 150 days), the animals were killed. Blood was collected, and bones underwent densitometric and biomechanical analyses. RESULTS: After castration, the male rats demonstrated low gain in body weight compared to females (P < .05). Male and female castrated animals presented serum concentrations of sex steroid hormones lower than the control group (P < .05). Bone mineral density and biomechanical properties of the L4 vertebrae and femur were reduced earlier in females than in males (P < .05). However, mandibles were affected only in the male rats at the most chronic experimental period. CONCLUSION: Hypogonadism promotes alterations in the mandible over chronic periods, especially in males, and these alterations could be minimized by hormone treatment.

Periodontal status in men with hypergonadotropic hypogonadism: effects of testosterone deficiency.

BACKGROUND: The purpose of this clinical study was to evaluate the possible influence of testosterone hormone on common clinical measurements of periodontal disease in men with hypergonadotropic hypogonadism. METHODS: Twenty-four hypergonadotropic hypogonadal men (H) and 24 systemically healthy men (S) were divided into two groups as chronic periodontitis and clinically healthy controls after clinical examinations and radiographs. The H group consisted of 12 control (H/C) and 12 chronic periodontitis (H/P) patients, and the S group consisted of 12 control (S/C) and 12 chronic periodontitis (S/P) patients. Plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing depth (PD), and clinical attachment loss (CAL) scores were recorded. RESULTS: The mean of all clinical parameters (PI, GI, BOP, PD, and CAL) were significantly (P<0.05) higher in periodontitis groups (H/P and S/P) than controls (H/C and S/C). There were no significant differences in the PD and CAL scores between periodontitis groups (S/P and H/P). The mean of GI and BOP scores were statistically higher in the H/P group than the S/P group (P<0.05). There was a negative correlation between GI and free testosterone levels (r=-0.794; P<0.05). CONCLUSION: According to these results, serum testosterone levels may possibly influence periodontal disease in men, and testosterone may have an inhibitory effect on gingival inflammation.

Microcephaly, hypergonadotropic hypogonadism, short stature, and minor anomalies: a new syndrome.

Four sibs, three males and one female, had microcephaly, hypergonadotropic hypogonadism, short stature, and multiple congenital anomalies. They had five normal sibs and consanguineous parents. Findings in the affected sibs also included a narrow forehead, synophrys, micrognathia, abnormally folded pinnae, early loss of teeth in three, cubitus valgus in two, genu valgum, gynecomastia, and undescended testes in one. All sibs had normal chromosomes. Results of tests for growth hormone release and adrenocortical function were normal. Luteinizing hormone releasing hormone (LHRH) and human chorionic gonadotropin (hCG) stimulation tests were consistent with primary gonadal failure. Testicular biopsy, performed on two affected males, was normal in one and showed focal atrophy with decreased spermatogenesis in the other. The patients manifest a phenotype different from all other known types of hypergonadotropic hypogonadism and appear to represent a new MCA/MR syndrome.

[Relation between hypogonadism and malocclusion in beta-thalassemia major patients: analysis of 122 subjects]. / Relazione tra ipogonadismo e malocclusione dentaria in pazienti affetti da beta-talassemia major. Studio su 122 pazienti.

AIM: The type of malocclusion most often seen in beta thalassemic patients is represented by Angle's II class, which however cannot be considered significant in the patients studied in this research. The only causal factor indicated by medical literature for this pathology is medullary hyperplasia due to inefficient erythropoiesis which occurs in patients transfused at low hemoglobin levels. The aim of this research is to evaluate the influence of other factors as well, particularly sexual development, the level of seric ferritin, ALT, and age at first transfusion. METHODS: One-hundred and twenty-two b thalassemic patients and 39 homozygotes, aged between 16 and 27, undergoing treatment at the "Ospedale Regionale per le Microcitemie di Cagliari", have been analysed. RESULTS: The results of the statistic analysis have shown that hypogonadism can play an important role in determining malocclusions in male beta thalassemic patients (Odds ratio 4,5; CI 1,5-13). No other factor has shown any statistically relevant influence on dental occlusion. CONCLUSION: It would therefore be interesting to further investigate the hormonal mechanisms that can alter bone development in thalassemic youngsters: the prevention of such alterations will surely contribute to improving the quality of life in these patients, particularly now that their life expectancy has been significantly extended by the progress made in transfusional therapy and ferrochelation.

Telltale teeth: Idiopathic Hypergonadotropic Hypogonadism.

UNLABELLED: The detection of any atypical extraoral or intraoral features warrants a thorough investigation, even if the patient is asymptomatic or unaware of these. At times, dental findings help in the diagnosis of an underlying systemic problem. These findings may or may not be associated with any syndrome. Thus, thorough examination and exhaustive investigations should be carried out for every atypical finding to ensure optimal oral and general health for the patient. CASE DESCRIPTION: This is a case report of seventeen year old male who presented with peculiar/atypical dentition which 'told the tale' and led to the diagnosis of underlying endocrinological problem about which the parents were totally unaware. The patient was short with central obesity and microcephaly. Intraorally, there was presence of thirty six microdonts. Consultation with pediatrician and endocrinologist, and thorough investigations confirmed the condition to be of 'Idiopathic Hypergonadotropic Hypogonadism'. The patient underwent not only oral rehabilitation, but also timely consultation and treatment from a pediatrician and an endocrinologist.

Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A encoding the catalytic subunit of polymerase III.

We describe a 33-year-old male patient with mental retardation and cerebellar ataxia whose brain magnetic resonance imaging (MRI) showed diffuse central hypomyelination. The associated hypogonadotropic hypogonadism and hypodontia were consistent with the clinical diagnosis of 4H syndrome. Two compound heterozygous mutations in POLR3A were found: p.Met852Val and p.Asn1249His. MRI of the brain showed cerebellar atrophy, atrophy of the corpus callosum, and diffuse hypomyelination extending as far as the U-fibers, with preservation of the basal ganglia. T2 hyperintensity was observed in the bilateral middle cerebellar peduncles. The patient showed almost normal development until 4-5years of age. After 25years of age, the patient showed a gradual but consistent motor and cognitive deterioration. We demonstrated the involvement of the corticospinal tract electrophysiologically, but peripheral nerve conduction was normal. Although this disease may start very early in life, the clinical course in the present case suggests that brains that initially appear to have developed normally may show dysfunction later in life, although the pathophysiological bases for this dysfunction may not be evident on MRIs.

A case with central and peripheral hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) plus cataract.

Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) is a rare disease, characterized by both central and peripheral hypomyelination. We describe a 21-year-old male with mildly progressive ataxia, mental retardation, pituitary hypogonadotropic hypogonadism, delayed dentition, and cataract. Brain magnetic resonance imaging showed hypomyelinated white matter, cerebellar atrophy, and a thin corpus callosum. The literature suggests that abnormal findings upon sural nerve biopsy may indicate peripheral hypomyelination, even in the absence of clinically and physiologically evident peripheral neuropathy. A sural nerve biopsy of this patient was normal, and this finding is further discussed. Taken together with previous reports, this case suggests that 4H syndrome can be regarded as a spectrum disorder, the cardinal signs of which may be central hypomyelination, ataxia, hypogonadotropic hypogonadism, and hypodontia.

New case of 4H syndrome and a review of the literature.

Different pathologic processes (especially demyelination, hypomyelination, and combinations of these) may underlie leukoencephalopathies. Leukoencephalopathies pose a particular diagnostic problem when they occur in children. To seek associated, non-neurologic signs is of fundamental importance in hypomyelinating leukoencephalopathies, because these can help clarify the diagnostic picture. Two new types of leukoencephalopathy have emerged, one classified as ataxia, delayed dentition, and hypomyelination, and the other as hypomyelination with hypogonadotropic hypogonadism and hypodontia. Initially described as distinct entities, they were recently brought together in the Online Mendelian Inheritance in Man database under a single code. However, the literature describes only two patients with the characteristics of both these clinical pictures. We present the extended clinical and neuroradiologic follow-up of a patient with ataxia, delayed dentition, and hypomyelination, as well as hypogonadotropic hypogonadism. This patient reinforces the idea that the two syndromes should actually be considered the same disorder, and prompted us to conduct a critical review of the literature on disorders in which hypomyelinating leukoencephalopathy is associated with cerebellar atrophy or hypogonadism.

A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism.

CONTEXT: Mandibuloacral dysplasia (MAD) is an autosomal recessive progeroid disorder associated with type A (partial) or B (generalized) lipodystrophy and is due to mutations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) genes. OBJECTIVE: The objective of the study was to report a novel syndrome with some overlapping features with MAD. RESULTS: We report seven patients with mandibular hypoplasia, deafness, progeroid features (MDP), and associated lipodystrophy. These patients have similar features to MAD patients such as hypoplastic mandible, beaked nose, stiff joints, and sclerodermatous skin. However, the patients did not harbor any disease causing variants in LMNA or ZMPSTE24 and showed distinct characteristics such as sensorineural hearing loss and absence of clavicular hypoplasia and acroosteolysis. All males with MDP had undescended testes and were hypogonadal. One adult female showed lack of breast development. Skinfold thickness, dual-energy X-ray absorptiometry and whole-body magnetic resonance imaging for body fat distribution revealed a lack of lipodystrophy in a prepubertal female but a progressive loss of sc fat presenting with partial lipodystrophy in young adults and generalized lipodystrophy in older patients. CONCLUSIONS: Patients with MDP syndrome have a few overlapping but some distinct clinical features as compared with MAD, suggesting that it is a novel syndrome. The molecular basis of MDP syndrome remains to be elucidated.

Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia.

We identified four unrelated patients (three female, one male) aged 20 to 30 years with hypomyelination, pituitary hypogonadotropic hypogonadism, and hypodontia. Electron microscopy and myelin protein immunohistochemistry of sural nerves showed granular debris-lined clefts, expanded abaxonal space, outpocketing with vacuolar disruption, and loss of normal myelin periodicity. Reduced galactocerebroside, sphingomyelin, and GM1-N-acetylglucosamine and increased esterified cholesterol were found. This is a clinically homogeneous progressive hypomyelinating disorder. The term 4H syndrome is suggested.

Association of isolated hypogonadotropic hypogonadism, pronounced hypodontia and the Wolff-Parkinson-White syndrome.

Diagnosis of idiopathic isolated hypogonadotropic hypogonadism was made in a 22-year-old female patient referred for primary amenorrhoea. It was considered a separate entity from Kallmann's syndrome, because it was not accompanied by anosmia or other specific pleiotropic features. On the other hand, the patient showed severe hypodontia and an intermittent Wolff-Parkinson-White syndrome. To our knowledge, this association has never been reported before. This unusual phenotype points to a nonrandom association. However, no information in the literature is available to consider a new single gene defect or a contiguous gene syndrome.

Visual function in Laurence-Moon-Bardet-Biedl syndrome. A survey of 26 cases.

In 1984, 32 persons with Laurence-Moon-Bardet-Biedl syndrome (LMBB syndrome) were registered in Norway. Of these, 26 stayed for 10 days at the Frambu Health Centre, where they consulted a pediatrician, a psychologist, a dentist, a social worker, a geneticist, a teacher for the blind and an ophthalmologist. The ocular examination showed the eye disease in cases of LMBB syndrome to be homogeneous and fulminant tapetoretinal degeneration of the retinitis pigmentosa type.

Hypogonadotropic hypogonadism in a female with the Johnson-McMillin syndrome.

A case of hypogonadotropic hypogonadism associated with the Johnson-McMillin syndrome is presented. This is a rare, autosomal dominant disorder, characterized by variable degrees of alopecia and anosmia, conductive hearing loss, and increased dental caries. Until now hypogonadotropic hypogonadism has only been observed in affected men. Ovulation can be induced with gonadotropins and conception can be obtained, but because prenatal diagnosis is not as yet possible, oocyte donation should be offered as an alternative for procreation.