Johanson-Blizzard syndrome: a case report]

The Johanson-Blizzard syndrome is a rare autosomal recessive syndrome. This syndrome includes congenital aplasia of the cutis, aplasia of the alae nasi, bilateral hearing loss, dental malformations and pancreatic insufficiency. CASE REPORT: We report a sporadic case male infant from nonconsanguineous parents. He presented aplasia of the cutis and high anorectal malformation, associated with exocrine pancreatic insufficiency. A colostomy was performed at birth and anorectal atresia was corrected surgically at two months. Exocrine pancreatic insufficiency required immediate enzyme supplementation.     

Johanson-Blizzard syndrome

Johanson-Blizzard syndrome is an extremely rare ectodermal dysplastic disorder characterized by aplasia or hypoplasia of alae nasi, midline scalp defects, growth retardation, varying degrees of mental retardation, hypothyroidism, exocrine pancreatic insufficiency and congenital deafness. This condition is supposed to be an autosomal recessive disorder. We are reporting a female neonate with the characteristic features and an uncommon less emphasized feature viz. café-aulait spots.     

The GHRH test in Turner's syndrome

GHRH test was performed in 11 girls suffering from Turner's syndrome ranging in age from 5.6-13.5 years. GH peak resulted lower than 10 ng/ml in three subjects, who had also shown reduced GH values after two conventional pharmacological stimuli (L-dopa- and insulin-induced hypoglycemia) and a value of mean GH concentration over 24 hours lower than 3 ng/ml. Both GH peak and area under the curve were not correlated with height, height velocity, bone age/chronological age ratio, GH peak after conventional pharmacological stimuli and mean GH value of spontaneous secretion. The comparison with the results of GHRH test in other kinds of short stature evidenced in girls with Turner's syndrome the presence of GH values (peak and area under the curve) higher than those in subjects with "classical" GH deficiency, lower than those in "short normal stature" and similar to those in subjects with "non classical" GH deficiency. In conclusion, our data suggest, even if within a certain variability of the responses, a possible involvement of GH deficiency to the pathogenesis of short stature in Turner's syndrome, suggesting the existence of a prevalent hypothalamic nature of GH deficiency.     

A familial syndrome of isolated "aplasia" of the anterior pituitary. Diagnostic studies and treatment in the neonatal period

A male newborn infant developed hypoglycemia, collapsed, and convulsed at eight hours of age. The diagnosis of pituitary "aplasia" was suspected, because of a previously affected female sibling, and treatment with glucocorticoids was instituted. Diagnostic studies revealed a deficiency of thyrotropin, growth hormone, and prolactin. He is now six months of age and is thriving on replacement therapy. Analysis of previous reports of this entity indicates that isolated "aplasia" of the anterior pituitary is a genetic syndrome with an autosomal recessive mode of transmission. The course in this patient suggests that this disorder, if diagnosed, is amenable to therapy.     

Johanson-Blizzard综合征一例及文献复习

目的 提高对Johanson-Blizzard综合征(JBS)的临床和诊断特点的认识.方法 讨论1例患儿的临床表现及诊断过程,运用基因检测的结果对诊断加以明确.并综合其他28例有详细临床资料的病例进行分析.结果 本例为女性,1岁9个月,以"脂肪泻"收治入院,出生后伴有肛门闭锁、鼻翼发育不全.现生长发育落后,智力发育落后,伴有头发稀疏及少牙畸形;便常规镜检脂肪球(++),血脂肪酶、淀粉酶及胰岛素、C肽水平偏低;腹部CT扫描见胰腺组织为脂肪组织替代;UBRI基因检测发现杂合错义突变,确诊JBS.在包括本例共计29例病例分析中,胰腺外分泌功能不全和鼻翼发育不全最为常见,分别为21例(72.4%)和27例(93%);18例(62%)伴有生长发育异常;17例(59%)伴有神经性听觉减退或丧失;头皮缺损和头发稀疏或异常卷曲分别有20例(69%)和13例(44.8%);甲状腺功能低下13例(44.8%);牙齿畸形13例(44.8%);肛门闭锁6例(21%).但是近亲结婚并不常见(3/29,10.3%).结论 JBS是一种罕见的、伴有独特先天性多发畸形的遗传性疾病,其特征表现是先天性胰腺外分泌不足伴有鼻翼发育不全或缺失,可以通过典型临床表现及UBRI基因检测加以明确.

Abstract：

Objective To study the clinical characteristics and diagnosis of the Johanson-Blizzard syndrome. Method The clinical characteristics and diagnosing procedure of 1 case with Johanson-Blizzard syndrome were analyzed, and genetic analysis was made in diagnosing procedure, and 28 cases of JohansonBlizzard syndrome with detailed clinical data were reviewed and analized. Result A one year and nine months old girl, who was initially admitted to the hospital because of fatty diarrhea and increased frequency of defecation. Imperforate anus, and aplastic alae nasi was noticed after birth. On physical examination,short stature, mental retardation, tooth abnormalities and scalp defects were observed. Fat globule was found by routine stool test. Serum biochemistry showed an exocrine and endocrine pancreatic insufficiency, CT scan of the abdomen demonstrated fatty replacement of the pancreas, UBRI gene analysis showed heterozygous for two missense changes. In all 29 cases, exocrine pancreatic insufficiency ( 72. 4% ) and hypoplasia of the alae nasi ( 93% ) were the most common clinical manifestations, and sensorineural hearing 1oss(59% ), scalp defects (69%) and hair thinning or upsweep of the hair (44. 8% ), hypothyroidism (44. 8% ), absence of permanent teeth (44. 8% )and imperforate anus(21% ) were also very common, but did not include consanguineous marriage of paerents( 10. 3% ). Conclusion Johanson-Blizzard syndrome is a rare autosomal recessive multisystem disorder, it is characterized by the association of congenital exocrine pancreatic insufficiency and hypoplasia or aplasia of the nasal wings, and can be diagnosed by clinical characteristics and UBRI gene analysis.     

Growth hormone deficiency is not associated with impaired vagal cholinergic nervous system activity in children

Central cholinergic mechanisms mediate release of growth hormone (GH) as well as peripheral secretion of pancreatic polypeptide (PP). To determine if impaired ability to secrete GH is associated with defective PP response, we studied the PP, epinephrine, and norepinephrine responses to insulin-induced hypoglycemia in 31 children evaluated for GH deficiency by insulin-arginine stimulation (IATT) and 24-h integrated concentrations of GH (IC-GH). Eleven patients had normal GH by IATT and IC-GH (controls), 10 patients had normal GH by IATT but subnormal IC-GH, 10 patients had GH deficiency by both IATT and IC-GH. PP levels peaked at the time of glucose nadir, and remained elevated for 20 min thereafter. The peak PP and incremental PP change from baseline were not significantly different among the three groups. The log peak PP response was inversely correlated with the glucose nadir (r = -0.5, p less than 0.005). Peak PP levels were also significantly correlated with the peak epinephrine levels (r = 0.6, p less than 0.001) but not with norepinephrine. Our findings suggest that 1) GH deficiency disorders are not associated with impaired vagal cholinergic response to hypoglycemia; 2) in children the magnitude of PP response is inversely related to the degree of hypoglycemia; and 3) the peripheral hormonal manifestation of autonomic nervous system responses to hypoglycemia as measured by PP and epinephrine levels are closely correlated.     

The catecholamine response to hypoglycemia in children with isolated growth hormone deficiency syndromes and multiple pituitary hormone defects

We examined the catecholamine response to insulin-induced hypoglycemia in 46 short children evaluated for growth hormone (GH) deficiency by both pharmacologic stimulation and integrated concentration of GH. Twelve patients had quantitatively normal GH secretion by both pharmacologic stimulation and integrated concentration of GH (GHNORM). Twenty-two patients had normal GH to pharmacologic stimulation but subnormal integrated concentration of GH (GHND). Twelve patients had GH deficiency by both tests (GHD): six had isolated GH deficiency (GHD type 1) and six had multiple hormone deficiencies (GHD type 2). There was no significant difference between the peak epinephrine, norepinephrine, and cortisol responses of GH-NORM, GHND, and GHD type 1 patients. The mean peak epinephrine response of GHD type 2 patients was significantly lower (564 +/- 561 pg/ml, p less than 0.03) compared to the other patient groups. There was no significant difference between the peak norepinephrine levels between GHD type 2 patients and the remaining groups. There was no correlation between decrease in blood glucose and either increase in growth hormone, catecholamine, or cortisol concentrations. There was a significant correlation between log peak epinephrine and peak cortisol response (r = 0.53, p less than 0.0002) of the 46 subjects. Neither the basal nor stimulated catecholamine levels correlated with the integrated concentration of cortisol. We conclude that isolated GH deficiency is not associated with impairment of the catecholamine response to hypoglycemia; impairment of the epinephrine response to hypoglycemia is only associated with multiple pituitary hormone deficiencies; in children, the degree of glucose lowering is not correlated with the magnitude of peak GH, catecholamine, or cortisol responses.     

Effect of growth hormone treatment on hypoglycemia in a patient with both hepatic glycogen synthase and isolated growth hormone deficiencies

A 7 year-old boy presenting with growth retardation, fasting hypoglycemia and ketoacidosis was diagnosed as having both idiopathic growth hormone (GH) deficiency and hepatic glycogen synthase (GS) deficiency caused by a homozygous mutation in exon 5 of the liver glycogen synthase gene (GYS-2). After four years of treatment with recombinant human GH, height increased from -4.9 SDS to -2.05 SDS which is near his target height of -1.6 SDS. The GH treatment, however, did not prevent the fasting hypoglycemia. Blood glucose levels were only normalized after avoiding fasting intervals of more than five hours and the frequent feeding of protein-rich meals according to the guidelines for treatment of hepatic GS deficiency.     

Hypoglycemia in hypopituitary children.

Fifty-two children with growth hormone (GH) deficiency were examined for factors that might influence development of hypoglycemia. Symptomatic and asymptomatic hypoglycemia occurred with equal frequency in children with isolated GH and multiple anterior pituitary deficiencies. Of 52 children, nine (17%) had symptomatic hypoglycemia and 14 (27%) had asymptomatic hypoglycemia. Symptomatic hypoglycemia was more frequent in children who were both young (less than 4 years of age) and lean (elevated height age/weight age [HA/WA] ratio). With HGH therapy, these children had decreases in HA/WA ratios and improvement in carbohydrate homeostasis. Insulin responses to oral glucose and intravenous arginine administration were substantially lowered in children with symptomatic hypoglycemia, A deficiency of gluconeogenic substrate or impairment of amino acid mobilization may be a factor in the development of hypoglycemia in hypopituitarism similar to that postulated for ketotic hypoglycemia.     

Pituitary stalk transection syndrome]

BACKGROUND: Pituitary stalk transection is a non-negligible cause of growth hormone (GH) deficiency. POPULATION AND METHODS: We studied 22 children (13 boys, nine girls) aged at the first clinical manifestations from 2 days to 10 years (average = 5.33 +/- 2 years). Pituitary stalk transection was assessed by the means of magnetic resonance imaging (MRI). The children's past history showed fetal distress in 12 cases (54.5%), cranial trauma in three (13%) and a midline anomaly in three (13%). The first clinical manifestations were neonatal hypoglycemia (two cases), decreased growth velocity (18 cases) and diabetes insipidus (two cases). RESULTS: GH deficiency was complete, present from the onset in 19 of 22 cases and isolated in four. Fifteen of 22 cases had adreno-corticotrophic hormone (ACTH) and thyroid stimulating hormone (TSH) deficiency. Diabetes insipidus was present in six cases and revealed the syndrome in two. All children older than normal age of puberty (n = 10) had gonadotropin deficiency. In our study, these hormonal anomalies progressed from isolated GH deficiency to multiple hormonal deficiencies. CONCLUSION: The recently described stalk transection syndrome is relatively frequent and should be suspected after cranial trauma or fetal distress syndrome. The outcome is progressive evolution towards panhypopituitarism and these patients require regular clinical survey and hormonal controls.     

Johanson-Blizzard syndrome

Johanson-Blizzard syndrome (JBS) is an autosomal recessively inherited disorder that is characterized by pancreatic insufficiency, a distinct appearance with hypo- or aplasia of the alae nasi and dental anomalies. We report on 3 patients with JBS who demonstrate the clinical variability of additional symptoms. In contrast to the common mental retardation in JBS we stress the outstanding intellectual abilities of one patient. It is important to realize the treatable dysfunctions in JBS. Specific therapy of e.g. pancreatic insufficiency and hypothyroidism can lead to a marked improvement of the clinical course. For the first time we discuss a possible sex influence. There is evidence that females have a better prognosis. The literature is reviewed, and aspects of differential diagnosis of JBS are considered.     

Growth hormone deficiency in patients with histiocytosis X

Twenty-two patients with biopsy proved histiocytosis X, aged 10 months to 14 years (median 2 years) at the time of diagnosis, were observed for 6 months to 13 years (median 4 years). One patient who had received 3000 rads irradiation directly to the hypothalamic-pituitary area had clinical and biochemical evidence of growth hormone deficiency and responded to GH therapy. Thirteen patients had normal stature, normal growth velocity, and no diabetes insipidus. The GH response to insulin-induced hypoglycemia was studied in three of these 13 patients (group 1), in three children with short stature and no diabetes insipidus (group 2), and in five patients with diabetes insipidus but normal stature and growth velocity (group 3). Peak GH responses were normal (greater than 5 micrograms/L) in all patients in groups 1 and 2, but three of the five patients in group 3 had subnormal GH responses to insulin-induced hypoglycemia and to arginine, L-DOPA/propranolol, and exercise. Their growth rates continue to be normal over 6 to 14 years follow-up. Thus, although impaired GH responses were observed in four of the 12 patients tested, true growth failure occurred only in association with direct hypothalamic-pituitary irradiation. This experience and the observation that GH deficiency was diagnosed in fewer than 1% of children with histiocytosis in Canada during a 15-year period (accounting for less than 1% of all children with GH deficiency) suggest that classic GH deficiency is not a common complication of histiocytosis unless direct hypothalamic-pituitary irradiation has been given.     

Dysregulation of the hypothalamic-pituitary-adrenal axis in short children with and without growth hormone deficiency

The effects of L-dopamine (LD) administration and insulin-induced hypoglycemia in adrenocorticotropin (ACTH) and cortisol secretion were studied in 14 short boys. LD caused moderate changes in both hormones. The four boys with isolated, idiopathic growth hormone (GH) deficiency (IGD) demonstrated a greater cortisol increase in response to hypoglycemia than the 10 boys with normal GH secretion. In at least some short children with IGD, abnormal regulation of the hypothalamic-pituitary-adrenal axis may be present.     

Child-onset growth hormone deficiency in adulthood. Transfer of patients from pediatric to adult endocrinology units

Treatment with growth hormone (GH) in adult-onset GH deficiency (AO-GHD) reverses its many metabolic alterations, modifying body composition, bone mass, several cardiovascular risk factors, and improving quality of life. In adult patients with a previous diagnosis of child-onset GH deficiency (CO-GHD), the lack of treatment also produces similar alterations, reversed by GH treatment. In patients with multiple pituitary hormone deficiency, the lack of GH is considered definitive, but in isolated GHD, the need for re-evaluation of the deficit is mandatory. The 'gold standard' test is insulin-induced hypoglycemia, after a wash-out period, and the criterion for GH therapy should be a GH (polyclonal-RIA assay) response less than 3 ng/ml. The initial recommended GH dose is lover than in children, and the dosage must be adjusted to maintain IGF-I levels in the normal range. We propose that decisions about patient recruitment, assessment, confirmation or reevaluation, information about new perspectives, disadvantages and benefits of GH therapy, and the beginning of treatment should be made in cooperation by pediatric and adult endocrinologists, so the patient receives all information from both medical teams, before being transferred to the adult endocrinology department.     

Novel <Emphasis Type="Italic">UBR1</Emphasis> gene mutation in a patient with typical phenotype of Johanson–Blizzard syndrome

Johanson–Blizzard syndrome is a rare autosomal recessive disorder, characterized by exocrine pancreatic deficiency and a wide range of other abnormalities. We present here an infant with failure to thrive, exocrine pancreatic deficiency, short stature and developmental delay, cutis aplasia on the scalp, aplasia of alae nasi, hypospadias, hypothyroidism, myxomatous mitral valve, and patent ductus arteriosus. Molecular studies revealed a novel homozygous nonsense mutation in exon 38 of the UBR1 gene, which confirmed the diagnosis of Johanson–Blizzard syndrome. It should be acknowledged that the combination of exocrine pancreatic insufficiency and nasal wing hypo-aplasia is pathognomonic for this syndrome. Prompt diagnosis and exact monitoring of the patients with JBS are required to avoid further complications.     

Hypoglycemia and cholestatic jaundice in congenital panhypopituitarism

The case of a female newborn who was first found to have severe recurrent hypoglycemia and then developed cholestasis with conjugated hyperbilirubinemia is presented. No infectious diseases, metabolic defects, or disease of the hepatobiliary system were found. Endocrinological investigations revealed panhypopituitarism. Hypoplasia or aplasia of the pituitary was suspected. Cholestasis and hyperbilirubinemia must be seen in association with growth hormone and cortisol deficiency in the context of pathogenesis.     

Concurrent pancreatic and growth hormone insufficiency in Johanson-Blizzard syndrome

Exocrine pancreatic insufficiency is one of the recognised features of the Johanson-Blizzard syndrome; other features include hypothyroidism, sensorineural deafness, aplastic alae nasi, developmental delay, and growth retardation. Twenty-one cases of the syndrome have been described to date. The child reported here was diagnosed in the neonatal period, but despite early pancreatic and thyroid replacement therapy his growth remained poor. Anterior pituitary function studies demonstrated growth hormone deficiency, subsequent administration of growth hormone has resulted in an improvement in his growth velocity. This feature has not been well documented and should be considered as a factor contributing to the growth retardation which is a constant feature of this syndrome.     

Robinow syndrome with growth hormone deficiency: treatment with growth hormone.

We describe a 5 years and nine months old boy who presented with facial features, vertebral anomalies and dwarfism consistent with Robinow syndrome. Investigations revealed growth hormone (GH) deficiency to be the cause of his dwarfism. We reviewed data on four other patients with Robinow syndrome from the Genentech National Cooperative Growth Study (NCGS). Results of GH testing on three out of four were available and showed GH deficiency. Recombinant human GH therapy in our patient and the three patients from the NCGS resulted in a significant increase in the growth rate per year. The cause of dwarfism in children with Robinow syndrome has hitherto not been studied. We propose its association with GH deficiency and that treatment with rhGH can result in a significant increase in the growth rate of these children.     

Neonatal hypoglycemia in a growth hormone registry: incidence and pathogenesis

OBJECTIVE: To examine the characteristics of infants with neonatal hypoglycemia treated with growth hormone (GH) in order to gain insights into factors aiding in the identification of and timely treatment of hypopituitary neonates. STUDY DESIGN: The National Cooperative Growth Study (NCGS) database was examined to identify infants with neonatal hypoglycemia started on GH by 6 months of age. 169 infants (100 males, 69 females) were found and their data analyzed for physical characteristics, the presence of other hormone deficits, and the diagnostic methods used. RESULTS: Mean +/- SD baseline length standard deviation score (SDS) was -1.5 +/- 1.8. 148/169 infants had hypopituitarism. Twelve had isolated GH deficiency (GHD). Nine had hypoglycemia without hypothalamic or pituitary pathology. Structural central nervous system (CNS) lesions and/or midline facial defects were present in 66/169. 55/100 males had micropenis. Although 158 infants had GHD, only 90 infants had it documented by stimulation testing (80) or a critical sample when hypoglycemic (10). Multiple hormone replacement therapy was necessary in 89% of the hypoglycemic infants. CONCLUSIONS: The great majority of these hypoglycemic infants had GHD, usually secondary to hypopituitarism. Over 1/3 had structural lesions of the hypothalamic-pituitary area or midline facial defects. Although lengths may be normal in these infants, physical features such as micropenis or cleft lip and/or palate should suggest pituitary dysfunction as the etiology of their hypoglycemia. A critical blood sample for GH taken during hypoglycemia is a quick and definitive diagnostic tool.