Duchenne muscular dystrophy, glycerol kinase deficiency, and adrenal insufficiency associated with Xp21 interstitial deletion

We report an interstitial deletion in the short arm of the X chromosome in a 6-year-old boy with Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal insufficiency, intermittent hypoglycemia, spasticity, psychomotor retardation, and growth delay. His mother also has this deletion in an X chromosome. From our findings, we propose that the human glycerol kinase locus and the human X-linked adrenal hypoplasia locus are in the Xp21 band.     

儿童复合型甘油激酶缺乏症

甘油激酶缺乏症（GKD）是一种少见的X染色体隐性遗传性代谢缺陷病,可分为单纯型和复合型。复合型又称为Xp21邻近基因缺失综合征,是由于位于Xp21区域包含有甘油激酶基因位点的不同大小片段基因的缺失所致,常见受累的相邻基因位点为先天性肾上腺发育不良（AHC）、杜氏肌营养不良（DMD）,临床表现取决于所累及的基因位点。尿液气相色谱-质谱（GC-MS）联用分析检出大量甘油可确定诊断。该文3例患儿均为男性,新生儿期即出现症状,均有先天性肾上腺皮质功能低下、高甘油尿症及杜氏肌营养不良相应的典型临床表现。经限制脂肪摄入及糖皮质激素治疗,肾上腺皮质功能不足症状明显改善,但肌无力进行性加重,随访中两例已死于肾上腺皮质危象。［中国当代儿科杂志,2007,9（5）：441-444］     

Complex glycerol kinase deficiency leads to psychomotor and body-growth failure

Complex glycerol kinase deficiency usually presents with Duchenne muscular dystrophy, glycerol kinase deficiency and adrenal hypoplasia congenital. We describe a follow-up patient with complex glycerol kinase deficiency who had appropriate intrauterine development, but who at 1 month of age manifested severe growth delay and psychomotor retardation. Targeted therapy did not bring about the regression of symptoms: both bodyweight and height were below the 3rd centile until 8 years of age, and his Griffith's Mental Development scale score was 71 at age 5 years.     

Phenotypic features of patients with congenital adrenal hypoplasia and glycerol kinase deficiency

Two unrelated boys with congenital adrenal hypoplasia and glycerol kinase deficiency were found to have similar features, including characteristic facies, testicular abnormalities, short stature, psychomotor retardation, and muscular dystrophy. The resemblance of these boys to other patients described in the literature suggests that a distinct phenotypic syndrome occurs in children with congenital adrenal hypoplasia and glycerol kinase deficiency.     

Gonadotropin Deficiency as a Significant Association of Complex Glycerol Kinase Deficiency: A Case Report with Cytogenetic and Molecular-Genetic Studies

A 6-year-old Japanese male patient with complex glycerol kinase deficiency (CGKD) is described. In addition to glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy, mental retardation and short stature, gonadotropin deficiency (GTD) was confirmed. The continuous stimulation of LHRH recovered the increment of serum LH and FSH values. Cytogenetic and molecular-genetic studies revealed a deletion in the Xp21 region which may involve many genes. Although a few cases of CGKD associated with GTD and/or cryptorchidism have been described, the cause of GTD has not been mentioned in the literature. The simultaneous occurrence of CGKD and GTD in these patients including ours may not be coincidental, but suggests the existence of a certain gene in the Xp21 region which may affect the development of hypothalamic LHRH secretory function. Therefore detailed and repeated evaluations of gonadotropin secretion are necessary in patients with CGKD.     

Familial X-linked adrenocortical hypoplasia association with androgenic precocity.

Four male cousins showed clinical and biochemical features of X-linked recessive congenital adrenocortical hypoplasia. In addition, they showed varying degrees of androgenic precocity. One was virilised at birth. Another showed advanced growth and skeletal maturation. The remaining two had genital measurements greater than normal for age and showed raised testosterone levels, although pituitary gonadotrophins seemed normal and there was no response to luteinising hormone-releasing hormone testing. It is suggested that in X-linked adrenal hypoplasia, intrauterine adrenal androgen deficiency results in abnormal priming of the pituitary ''gonadostat'', leading to an abnormal feedback with excess testosterone production and nonprogressive virilisation.     

Congenital adrenal hypoplasia and glycerol kinase deficiency

An unusual case of salt-wasting in a male infant is reported. The cause was a small X-chromosomal deletion within Xp21 resulting in the syndrome of congenital adrenal hypoplasia with glycerol kinase deficiency. This syndrome can readily be diagnosed by routine biochemical tests.     

Congenital Adrenal Hypoplasia and Glycerol Kinase Deficiency

ABSTRACT. An unusual case of salt-wasting id a male infant is reported. The cause was a small X-chromosomal deletion within Xp21 resulting in the syndrome of congenital adrenal hypoplasia with glycerol kinase deficiency. This syndrome can readily be diagnosed by routine biochemical tests.     

Endocrine disorders in septo-optic dysplasia (De Morsier syndrome) — evaluation and follow up of 18 patients

Septo-optic dysplasia (SOD) is characterized by hypoplasia of the optic nerve, various types of forebrain defects and hormonal deficiencies. We have studied the clinical and endocrinological characteristics of 18 such patients retrospectively to: (1) better define the endocrine abnormalities in children with SOD; and (2) to find approaches for the interdisciplinary long-term care of children with SOD. The children were seen at the Children's Hospital of the University of Munich from 1976 to 1992 (8 boys, 10 girls; age at initial presentation: 1 day–13 years of age, mean 1.9 years). Unilateral hypoplasia of the optic nerve was found in 7 cases, bilateral hypoplasia in 11. Sonographic, CCT or MRI yielded the following results: 4 of the patients had a cavum septum pellucidum, 3 patients had hypoplasia of the cerebellum, 1 aplasia of the corpus callosum and 1 aplasia of the fornix. An empty sella with or without an ectopic pituitary was seen in 4 cases. Height standard deviation score (SDS) at time of diagnosis was –4.0 to +0.4, mean –2.92. Endocrine deficiencies were present in all 11 patients who had undergone endocrinological investigations. Seven patients suffered from isolated growth hormone (GH) deficiency or multiple hypopituitarism. One had diabetes insipidus centralis, 2 had hypogonadotropic hypogonadism, 1 had hypothyroidism and 2 adrenal insufficiency. Hypothalamic testing was performed only in a subset of patients: in 5 of 11 children tested a thyrotropin releasing hormone (TRH test), in two out of nine a gonadotropin releasing hormone (GnRH) test, and in three out of six GH releasing hormone (GHRH) test yielded abnormal results. High prolactin levels were measured in two out of five patients.Conclusion SOD is characterized by optic nerve hypoplasia and a variety of endocrine deficiencies. In addition, forebrain malformations are present in most SOD patients. Hormonal disorders are present in some SOD patients which may be of hypothalamic origin and need to be investigated systematically.     

Complex glycerol kinase deficiency: An X-linked disorder associated with adrenal hypoplasia congenita

Complex glycerol kinase deficiency (GKD) results from the contiguous deletion on Xp21 of all or part of the gene for glycerol kinase together with that for adrenal hypoplasia congenita (AHC) and/or Duchenne muscular dystrophy (DMD). The authors present the case of a newborn whose initial issues were refractory hypoglycaemia along with hyponatremia and hyperkalemia. He also had low serum cortisol levels and raised urinary excretion of glycerol and required steroid supplementation. His creatinine phosphokinase (CPK) levels were normal. Molecular studies revealed a contiguous Xp21 deletion. Therapy in such cases must be prompt and includes correction of hypoglycaemia and dyselectrolytemia, a low fat diet and steroid replacement.     

Variable presentation of X-linked adrenal hypoplasia congenita

We present a family with X-linked adrenal hypoplasia congenita (AHC) due to a truncation mutation in the DAX1 gene. The three patient reports demonstrate variable clinical and biochemical features at presentation. They presented with adrenal crises at 3 years, 4 weeks, and 3 weeks. Mineralocorticoid deficiency preceded glucocorticoid deficiency in patient 3 and an early ultrasound indicated normal sized adrenal tissue. Genetic analysis showed that potential female carriers were unaffected.     

Infantile glycerol kinase deficiency— a condition requiring prompt identification

Infantile glycerol kinase deficiency (GKD) is an X-linked genetic disease characterized clinically by adrenal insufficiency and muscular dystrophy. The enzyme defect leads to increased levels of glycerol in blood and urine, which can be used for diagnosis. Without recognition of this condition, the chances for life-saving steroid treatment and for genetic counselling are missed. We report clinical, endocrinological, biochemical, and morphological findings in two non-related boys. One of them died in early infancy. The other is thriving at the age of 2 years although he is suffering from a myopathy not distinguishable from Duchenne muscular dystrophy. We discuss when to suspect and how to confirm the diagnosis of infantile GKD, and under what precautions the condition is detectable by commonly used screening procedures for inborn errors of metabolism.     

Hearing loss in children with type 1 diabetes

OBJECTIVE: To examine the auditory function in a group of children with type 1 diabetes, and to study the association between hearing impairment and duration of illness, metabolic control and diabetic complication. METHODS: Sixty-three diabetic patients below the age of 18 attending the university hospital in Khartoum, Sudan were investigated together with 63 age and sex matched non-diabetic controls. Pure-tone audiometric tests were performed using an Amplaid 300 clinical audiometer in a soundproof room. Both air and bone conduction were tested at frequencies between 250-8000 Hz and 250-4000 Hz respectively. Hearing impairment was noted at auditory threshold above 25 dB in any frequency and the magnitude of hearing loss was assessed according to auditory threshold in conversational frequencies only. RESULTS: The hearing acuity was lower in the diabetic patients than in the control subjects in all tested frequencies, but the differences achieve statistical significance only at middle and high frequencies. The hearing loss was symmetrical, generally mild, and affects both sexes equally. Duration of diabetes, HbA1c concentration, and angiopathic complications showed positive correlation with the increased hearing thresholds; while, age at onset, insulin dose per day, presence of neuropathy, and frequency of DKA and hypoglycaemic episodes were not associated. CONCLUSION: Hearing loss occurs early in diabetic children and is related to the duration of the disease and the degree of metabolic control. Strict glycemic control might prevent or delay this complication.     

Sensorineural hearing loss in primary antibody deficiency disorders

To evaluate the hearing function in patients affected by primary antibody deficiency disorders. Forty-seven patients, 25 of whom were affected by X-linked agammaglobulinemia and 22 of whom were affected by common variable immunodeficiency were evaluated with audiologic tests that included pure tone audiometry, acoustic immittance assessment and auditory brainstem-evoked response. Eighteen patients (38%), 7 with X-linked agammaglobulinemia and 11 with common variable immunodeficiency, showed sensorineural hearing loss, bilateral in 12 and unilateral in 6. Our data underline the high frequency of hearing loss in patients with antibody deficiency and suggest that a systematic audiologic evaluation should be part of the clinical care of these patients.     

Mumps meningoencephalitis effect on hearing

Sensorineural hearing loss is an important complication of mumps. Audiologic tests of 26 children with mumps meningoencephalitis, 25 uncomplicated mumps cases and 20 control cases were performed, and hearing level thresholds at speech and high frequencies were determined. The mean hearing level thresholds in the mumps meningoencephalitis group were higher than those of mumps cases at frequencies from 6,000 to 18,000 Hz in the right ear and at 250 and from 4,000 to 18,000 Hz in the left ear (P < 0.05). Mumps meningoencephalitis cases had higher mean hearing thresholds than did control groups at all frequencies other than 125 and 250 Hz in the right ear and 10,000 Hz in the left ear. The mean hearing thresholds of mumps cases were higher than those of control group at frequencies of 1,000 and 4,000 Hz in the right ear and 1,000 and 10,000 Hz in the left ear (P < 0.05). These results show that mumps meningoencephalitis causes a higher risk of hearing loss than does mumps.     

Development of fetal hearing

Previous research has revealed that the human fetus responds to sound, but to date there has been little systematic investigation of the development of fetal hearing. The development of fetal behavioural responsiveness to pure tone auditory stimuli (100 Hz, 250 Hz, 500 Hz, 1000 Hz, and 3000 Hz) was examined from 19 to 35 weeks of gestational age. Stimuli were presented by a loudspeaker placed on the maternal abdomen and the fetus's response, a movement, recorded by ultrasound. The fetus responded first to the 500 Hz tone, where the first response was observed at 19 weeks of gestational age. The range of frequencies responded to expanded first downwards to lower frequencies, 100 Hz and 250 Hz, and then upwards to higher frequencies, 1000 Hz and 3000 Hz. At 27 weeks of gestational age, 96% of fetuses responded to the 250 Hz and 500 Hz tones but none responded to the 1000 Hz and 3000 Hz tones. Responsiveness to 1000 Hz and 3000 Hz tones was observed in all fetuses at 33 and 35 weeks of gestational age, respectively. For all frequencies there was a large decrease (20-30 dB) in the intensity level required to elicit a response as the fetus matured. The observed pattern of behavioural responsiveness reflects underlying maturation of the auditory system. The sensitivity of the fetus to sounds in the low frequency range may promote language acquisition and result in increased susceptibility to auditory system damage arising from exposure to intense low frequency sounds.     

A Case With the Infantile Type of Glycerol Kinase Deficiency

A male infant with the infantile type of glycerol kinase deficiency is described. At six years of age, he showed proximal dominant muscle atrophy and weakness, addisonian pigmentation and mental retardation. Laboratory investigations revealed muscular dystrophy, adrenal insufficiency and glycerol kinase deficiency. He has a small deletion in a band (Xp21) of the X chromosome. The clinical, biochemical and genetic findings in this patient are reported.     

Development of fetal hearing

Previous research has revealed that the human fetus responds to sound, but to date there has been little systematic investigation of the development of fetal hearing. The development of fetal behavioural responsiveness to pure tone auditory stimuli (100 Hz, 250 Hz, 500 Hz, 1000 Hz, and 3000 Hz) was examined from 19 to 35 weeks of gestational age. Stimuli were presented by a loudspeaker placed on the maternal abdomen and the fetus's response, a movement, recorded by ultrasound. The fetus responded first to the 500 Hz tone, where the first response was observed at 19 weeks of gestational age. The range of frequencies responded to expanded first downwards to lower frequencies, 100 Hz and 250 Hz, and then upwards to higher frequencies, 1000 Hz and 3000 Hz. At 27 weeks of gestational age, 96% of fetuses responded to the 250 Hz and 500 Hz tones but none responded to the 1000 Hz and 3000 Hz tones. Responsiveness to 1000 Hz and 3000 Hz tones was observed in all fetuses at 33 and 35 weeks of gestational age, respectively. For all frequencies there was a large decrease (20-30 dB) in the intensity level required to elicit a response as the fetus matured. The observed pattern of behavioural responsiveness reflects underlying maturation of the auditory system. The sensitivity of the fetus to sounds in the low frequency range may promote language acquisition and result in increased susceptibility to auditory system damage arising from exposure to intense low frequency sounds.     

High frequency hearing loss in Ullrich-Turner syndrome

A total of 38 patients with Ullrich-Turner syndrome underwent standard otological and audiometric evaluation as well as high frequency audiological tests. Some 26 (68.4%) patients had a history of middle ear infections, and ten (26.3%) had required otolaryngological surgery. Conventional audiometry (125–8000 Hz) demonstrated normal hearing in only 25 of the ears (33%); between 500–4000 Hz, 16 ears (21.0%) had a mixed type and eight ears (10.5%) had conductive hearing loss. High frequency audiometry (8–18 kHz) revealed sensorineural hearing loss in 98.7% of the ears. Our results for conventional audiometry are in accordance with the literature. Conclusion The detection of a high prevalence of hearing loss in the high frequency range brings a significant new perspective to the pursuit of the aetiology of ear and hearing problems in Ullrich-Turner syndrome. This pathology seems to be a premature variant of presbycusis and it may underlie future hearing impairment which will come to clinical attention only after it progresses to conventional testing frequencies. While further studies are underway to evaluate this aspect, routine otological and audiological follow-up of patients with Ullrich-Turner syndrome is warranted from the time of diagnosis. Received: 1 December 1999 and in revised form: 31 March 2000 / Accepted: 4 April 2000     

Acute adrenal insufficiency in the newborn]

Neonatal acute adrenal insufficiency is a rare condition. Congenital adrenal hyperplasia with 21-hydroxylase defect appears to be the most frequent cause, but the neonatal screening has improved its potential severe outcome. The other causes and the various clinical presentations have been exposed, with a special reference to the salt-wasting syndrome. Among them, the severity of X-linked adrenal hypoplasia congenita (AHC) deserves special attention. Two other causes of adrenal hypoplasia have been recently discovered, i.e. a mutation of the SF-1 gene and the syndrome IMAGe. Adrenal insufficiency secondary to ACTH deficiency is often unrecognised despite the risk of severe seizures and hypoglycaemia with brain damage. Finally, the hormonal diagnostic testing and the main therapeutic approach by corticosteroids have been indicated. The aim of this work is to focus the attention of paediatricians who examine a newborn because the risk of delayed diagnosis and fatal outcome may be limited if the clinical symptoms are soon recognized.