An Italian family affected by autosomal dominant microcephaly with chorioretinal degeneration

PURPOSE: We studied an Italian family affected by the autosomal dominant form of microcephaly and chorioretinal degeneration that was characterized by various degrees of clinical expression. METHODS: An ophthalmologic examination, including visual acuity, visual field testing, an electroretinogram, and fundus photography, and a neurologic examination, including neurodevelopmental status and neuroimaging studies, were performed for all subjects. Skeletal radiography, chromosome studies, and serologic investigations were also performed. RESULTS: In this family, only two of the six affected members had an association of microcephaly, myopia, and chorioretinal degeneration. The other family members showed microcephaly, slight mental retardation, and short stature, but not chorioretinopathy. CONCLUSIONS: The significant finding in members from this dominant pedigree of microcephaly was the association of short stature and high myopia, heretofore seen only in families with recessive microcephaly. These findings could be useful for genetic counseling in the apparently isolated forms of microcephaly with chorioretinopathy.     

Two cases of coxsackie B2 infection in neonates: Clinical,virological, and epidemiological aspects

Two cases of neonatal coxsackie virus B2 infection are described. One infant presented with meningitis and enteritis, the other with rhinitis, meningoencephalitis, and enteritis. Both infants made good recoveries. The virus infection could also be demonstrated in all nonimmune family members, most of whom gave a history of recent mild febrile disease (pharyngitis, diarrhea). Enterovirus infections may be suspected in cases of neonatal meningitis or myocarditis associated with gastrointestinal signs, especially 1. when it is during the hot season July-October, 2. when there has been febrile illness in other family members recently. For an effective and rapid isolation of the agent, rectal swabs or stool specimens not only from the patient, but also from household contactss should be sent to the virus laboratory on several consecutive days. Meningitic infection may be proved by anearly c.s.f. sample. For serodiagnosis a first blood specimen should be drawn as soon as possible, a second one some days later. The importance of rapid virological diagnosis and of stringent hygienic measures to prevent spread of the infection is stressed.     

Two families of Lowe oculocerebrorenal syndrome with elevated serum HDL cholesterol levels and CETP gene mutation

The ocuolocerebrorenal syndrome of Lowe (OCRL) is an X-linked recessive disorder which is characterized by renal tubular dysfunction, congenital cataracts, and cognitive impairment. In a review article by Charnas et al. (N Engl J Med 1991; 324: 1318-25), hypercholesterolemia, due to elevated highdensity lipoprotein cholesterol (HDLC) levels, was described as being highly prevalent in OCRL patients. This report prompted us to examine three OCRL children in two unrelated families and we confirmed the high prevalence of high serum HDLC levels in the patients (3/3). In addition, we found that their normal family members also had high serum HD-LC levels (5/7). Analysis of cholesteryl ester transfer protein (CETP) genes, which are now recognized as one of factors increasing serum HDLC levels, revealed the D442G mutation in exon 15 in 5 of 10 family members (1/3 of OCRL patients and 4/7 healthy family members), and no mutation of intron 14 G(+1)-to-A. The detected D442G mutation may be one of the causes in our two OCRL families; however, further studies, based on larger numbers of subjects, are needed to confirm these findings.     

Onset of cataract in early infancy associated with a 32G-->C transition in the iron responsive element of L-ferritin

We describe the onset of cataract in early infancy in a family with hereditary hyperferritinaemia-cataract syndrome. The two probands presented with isolated hyperferritinaemia and had developed cataracts at the age of 18 months. Two members of their family with high ferritin levels (1270-1450 microg/l) had suffered from cataract since childhood. The mutation responsible was a 32G-->C change in the lateral bulge of the stem structure of the iron responsive element of the L-ferritin subunit gene. Mutations at this level cause particularly high ferritin levels, whereas the age of cataract onset and its severity are controversial subjects. In our family, early ophthalmic examination ruled out the possibility that cataract was due to age-related persistence of high ferritin levels in the lens and suggested that other factors may modulate the phenotype. CONCLUSION: cataract may appear early in hereditary hyperferritinaemia-cataract syndrome and this syndrome should be suspected and ferritin levels measured in all cases of cataract in children, even when the onset is in early infancy.     

The Kenny syndrome,a rare type of growth deficiency with tubular stenosis,transient hypoparathyroidism and anomalies of refraction

One family (3 cases) with the Kenny syndrome and a second family (3 cases) with features of Kenny syndrome but lacking medullary stenosis are reported. The main symptoms in both families are proportionate dwarfism, cortical thickening of tubular bones, variable anomalies of the calvaria, anemia, transient hypoparathyroidism and variable ocular anomalies. The latter include microphthalmia, and moderate-to-severe myopia or hyperopia. In the first family there was medullary stenosis of most tubular bones. In the second family two cases exhibited mildto-moderate cortical thickening of tubular bones, but absent or mild medullary stenosis.Possible variability of the Kenny syndrome is discussed. Endocrine studies failed to demonstrate any permanent disturbance of parathormone or calcitonin metabolism, or GH deficiency. Pathogenesis remains unclear. Autosomal dominant inheritance seems to be likely.Presented in part at the Symposium to Honour the 60th Birthday of Prof. Dr. W. Lenz, Münster, February 1979     

A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly

We describe a three generation family with recurrent strokes and cataracts. The index case, a 14 year old boy presented with stroke at the age of 14 years and again 6 months later. His mother had long standing episodic headaches diagnosed as migraine. Grandmother was initially diagnosed with multiple sclerosis and had recurrent strokes at age 18 years and 49 years. MRI scanning showed a diffuse leukoencephalopathy with microhaemorrhages in all three individuals. All of the family members had cataracts but did not have retinal arterial changes. Sequence analysis of COL4A1 revealed the heterozygous missense mutation c.2263G→A in exon 30, responsible for a glycine-to-arginine substitution (p.Gly755Arg) in both the index case and mother. Grandmother died at the age of 73 years and DNA analysis was not possible. Mutation in COL4A1 should be considered in families with a history of autosomal dominant cerebral vasculopathy, even in the absence of porencephaly.     

Mutation in the X-linked RAB40AL gene (Martin-Probst syndrome) with mental retardation,sensorineural hearing loss,and anomalies of the craniofacies and genitourinary tract: a second case report

An X-linked neurodevelopmental disorder previously had been reported in only one family, associated with a p.D59G mutation in the RAB40AL gene that encodes a mitochondrial Ras protein. The three related males described had varying degrees of cognitive impairment, sensorineural hearing loss, short stature, dysmorphic facies, and other morphological defects. Conclusion: We herein present an unrelated 20-year-old male with similar manifestations also with p.D59G in the RAB40AL gene, which supports the existence of this condition previously coined as Martin-Probst syndrome (OMIM: 300519).     

A boy with atrophic thyroiditis of prepubertal onset,who was positive for TSH-binding inhibitor immunoglobulins

A 12 year old boy was admitted to our hospital because of short stature. From the age of 7, his growth velocity decreased and he manifested intolerance to low temperatures, hoarseness, dry skin, and slowness of thought and physical movement. On admission, his height was 129.8 cm (-3 s.d.) and his body weight was 43.2kg (-0.5 s.d.). His clinical features also included relaxation phase of tendon reflexes, periorbital puffiness and cold skin but no struma. His bone age was 9 years. His serum thyroxine (T₄), tri-iodothyronine (T₃), free T₄ and free T₃ were low, while his thyrotropin was high. He was positive for antithyroglobulin antibodies, antimicrosomal antibodies, and TSH-binding inhibitor immunoglobulins. He was diagnosed as having atrophic thyroiditis. We also determined the HLA haplotypes of his family members. His father's HLA haplotypes were A2, BW61(a) and A24, BW52(b), while his mother's haplotypes were A24, BW52(c) and A30, BW61(d). The HLA haplotypes of both the patient and his younger brother showed a and d, while the patient's elder brother's HLA haplotypes showed b and c. His family members all had normal thyroid function, but his father was positive for antimicrosomal antibodies. In summary, we describe a rare case where the onset of hypothyroidism was prepubertal, where the pathogenesis may have involved TSH-receptor blocking antibodies, and where the inheritance of the disease may have been from the paternal side of the family.     

ABNORMAL NEUTROPHIL CHEMOTAXIS IN A SYNDROME OF UNUSUAL FACIES, PROPORTIONATE SMALL STATURE AND SENSORINEURAL DEAFNESS-MUTISM

ABSTRACT. Two of 5 children in one family presented with unique facies, proportionate small stature and sensorineural deafness-mutism. One of the children who had a history of recurrent infections, was shown to have a defect of leukocyte chemotaxis. Although impairment of chemotaxis could not be demonstrated in the other affected sibling, it is unlikely that the association of a previously undescribed syndrome and a rare disorder of chemotaxis is a chance occurrence.     

Abnormal neutrophil chemotaxis in a syndrome of unusual facies, proportionate small stature and sensorineural deafness-mutism

Two of 5 children in one family presented with unique facies, proportionate small stature and sensorineural deafness-mutism. One of the children who had a history of recurrent infections, was shown to have a defect of leukocyte chemotaxis. Although impairment of chemotaxis could not be demonstrated in the other affected sibling, it is unlikely that the association of a previously undescribed syndrome and a rare disorder of chemotaxis is a chance occurrence.     

Pregnancy-exaggerated galactosemia and congenital cataracts

One child In a family and two children in another family had galactosemia and congenital cataract. Two of them had total soft cataracts while in one, cataract was less soft. In addition, they had mild lactosuria. The mothers of the affected children had significant lactosuria and mild galactosuria without cataracts. Fathers did not have galactosuria or lactosuria. Clinically unaffected siblings in one family had mild galactosuria and lactosuria. Pregnancy-exaggerated galactosemia was suspected in these two mothers who gave birth to children with congenital cataract. As an extension of this work, 5001 pregnant women were screened for galactose in urine just before the delivery of babies. Mild galactosuria was present in 54 (1.08%). Three children had congenital cataract and one had changes in posterior pole and cornea. Restriction of lactose by reducing intake of milk and milk products during pregnancy by mothers with galactosuria is recommended to avoid the birth of children with congenital cataract.     

Pseudohypoparathyroidism with normal serum calcium level.

A mildly obese 15-year-old boy had short stature with rounded facies and short, stubby hands and toes. He had the fully expressed syndrome of pseudohypoparathyroidism but was the only member of his family who had all the somatic characteristics of this disease. The serum parathyroid hormone level was substantially elevated. Urinary excretion of cyclic adenosine monophosphate and phosphate failed to increase following intravenous infusion of parathyroid hormone. However, he did not have hypocalcemia. The present entity is probably a transient form of pseudohypoparathyroidism with partial responsiveness of skeletal adenyl cyclase to parathyroid hormone.     

MRI T2*技术对中、重型β地中海贫血患者心脏及肝脏铁沉积状态的评估

目的：了解中、重型β地中海贫血患者体内铁沉积状况。方法：对39例中、重型β地中海贫血患者的输血、排铁的情况进行统计,检测患者体内铁蛋白水平,并运用MRI T2*技术检测心脏及肝脏铁沉积状况。结果：患者血清铁蛋白水平最低为1500 ng/mL,最高达 11491 ng/mL。肝脏铁重度沉积者15例（38%）,中度沉积者15例（38%）,轻度沉积者7例（18%）,正常者 2例（5%）。 心脏铁重度沉积者7例（18%）,轻度沉积者5例（13%）,正常者27例（69%）。1例出现心律紊乱症状,4例年龄超过20岁者均呈现性腺功能发育不全。大多患者因家庭经济原因未能进行规律输血及排铁治疗,且开始排铁时间较晚。患者血清铁蛋白水平与开始排铁的时间、剂量密切相关。结论：未进行早期规律的输血和排铁治疗的地中海贫血患者,体内铁的沉积发生年龄早,易早期出现重要器官的功能损害而引发相关并发症,应引起临床医师和患者家属的高度重视并制定相应的诊疗措施提高患者的生活质量。     

Spondylo-epiphyseal dysplasia with ocular changes

Two families with “new” types of spondyloepiphyseal dysplasias are reported. The disease(s) are characterised by spinal changes, capital femoral epiphyseal involvement and minor changes in other epiphyses. The eye complications consist of myopia, lattice degeneration of the retina, retinal detachment and cataracts. Short stature is a major feature in the first family and shortening of the hands and feet in the second.     

Familial simple ectopia lentis: a case study

Hereditary simple ectopia lentis affected nine patients in three generations of a family. Inheritance appeared to be autosomal dominant. Examination of 12 family members, employing body proportion measurements, chest x-ray, echocardiogram, and urinary cystine or blood methionine levels, revealed no evidence of any systemic disease. In all cases except two, lenses were bilaterally and superiorly dislocated. The degree of dislocation varied considerably among those affected, causing no visual disturbance in some and severely limiting visual acuity in others. Visual deficits were greatest in patients with intermediate degrees of dislocation. To date, the only known complications related to the dislocations have been two cases of bilateral cataracts. The indications for lensectomy in patients with ectopia lentis are reviewed.     

Psychological Problems in the Families of Japanese Insulin-Dependent Diabetes Mellitus (IDDM) Patients

Emotional stability of insulin-dependent diabetics is closely related to their metabolic control. We have already presented the psychological features of diabetic children at the 5 th International Beilinson Symposium. These results indicate that psychological problems are usually interactions with the patient's family. Family troubles derived from impaired interrelation are significant. From these points of view, counselling with the family based on a proper understanding of their relationship is absolutely necessary. We have had regular meetings for mothers with diabetic children in our clinic to discuss their psychological troubles. In this study we examined the frequency of poorly controlled patients in our clinic and analyzed the nature of their problems. We further summarized the opinion of family members which had been discussed in the above-mentioned meeting. Frequency of constantly poorly controlled patient was 8.1% (3/37) in male and 16.3% (8/49) in female. We report on our method' of approach to them.     

Phenotypic diversity in siblings with partial androgen insensitivity syndrome

Accepted 5 March 1997
The androgen insensitivity syndrome is a heterogeneous disorder with a wide spectrum of phenotypic abnormalities, ranging from complete female to ambiguous forms that more closely resemble males. The primary abnormality is a defective androgen receptor protein due to a mutation of the androgen receptor gene. This prevents normal androgen action and thus leads to impaired virilisation. A point mutation of the androgen receptor gene affecting two siblings with partial androgen insensitivity syndrome is described. One had cliteromegaly and labial fusion and was raised as a girl, whereas the other sibling had micropenis and penoscrotal hypospadias and was raised as a boy. Both were shown to have the arginine 840 to cysteine mutation. The phenotypic variation in this family is thus dependent on factors other than abnormalities of the androgen receptor gene alone.

     

Spread of methicillin‐resistant Staphylococcus aureus USA300 in a neonatal intensive care unit

Background: Reports of community‐associated methicillin‐resistant Staphylococcus aureus (CA‐MRSA) in neonatal intensive care units (NICU) and in otherwise healthy patients without obvious risk factors have been increasing in frequency. Described herein is a cluster of cases of CA‐MRSA USA300 strains in an NICU affecting infants, health‐care workers and the health‐care workers’ families. Methods: Infants and health‐care workers with infection and colonization due to MRSA between 1 January 2004 and 30 June 2005 in a tertiary care center NICU in San Antonio, TX were studied. Antimicrobial susceptibility testing and polymerase chain reaction detection of the mecA gene characterized the MRSA isolates. All MRSA cases were reviewed for clinical severity of infection and outcome. Results: During the 18 months studied, a total of four (0.6%) of 676 infants had CA‐MRSA bacteremia or colonization. One infant with necrotizing pneumonia died and three health‐care workers who directly cared for the infected infants developed soft‐tissue infections caused by CA‐MRSA. Four family members of two health‐care workers subsequently developed soft‐tissue infections. All of the analyzed isolates (eight of nine) belonged to pulsed‐field type USA300 and possessed Panton–Valentine leukocidin genes, which have been associated with severe skin and soft‐tissue infections, and necrotizing pneumonia. Conclusions: It is likely that the CA‐MRSA USA300 strain can be transmitted between NICU patients to health‐care workers and their family members. The CA‐MRSA cases reported here reinforce the virulence of CA‐MRSA USA300 strains and emphasize the need to embrace infection control practices designed to protect hospitalized patients, health‐care workers and their family members.     

Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency

A family is described in which the father and three (and probably all four) of his children had a decreased capacity for the oxidation of medium-chain fatty acids. One of the children suddenly died at the age of 16 months following an episode of a rapidly deteriorating Reye syndrome-like illness with hypoketotic hypoglycemia and dicarboxylic aciduria, but without any previous alarming symptoms. The eldest sibling had died at the age of 19 months under similar conditions. The other family members had always been healthy. On fasting, all affected family members accumulated in their plasma the medium-chain fatty acids octanoic, decanoic, and cis-4-decenoic acids. Their urinary organic acid excretion profile could be characterized as "dicarboxylic aciduria." A deficiency of medium-chain acyl-coenzyme A dehydrogenase was demonstrated in a postmortem liver sample of the index patient. Cultured fibroblasts from the father and the two healthy children had a decreased rate of [14C]octanoate oxidation. It is suggested that a deficiency of medium-chain acyl-coenzyme A dehydrogenase may lead to a life-threatening illness when other complicating factors such as diarrhea and vomiting result in an abnormal depletion of the body's glycogen stores. Careful monitoring of at-risk patients during a minor illness is necessary.     

Central core disease: clinical, pathological, and genetic features

Central core disease (CCD) is a dominantly inherited congenital myopathy allelic to malignant hyperthermia (MH) caused by mutations in the RYR1 gene on chromosome 19q13.1. Eleven individuals with RYR1 mutations are described. Four index cases showed features consistent with a congenital myopathy (hypotonia, delayed motor milestones, and skeletal abnormalities including congenital hip dislocation and scoliosis). All four cases and subsequently seven other family members were found to possess novel mutations in the RYR1 gene. The degree of disability varied from one clinically normal individual, to another who had never achieved independent ambulation (the only patient with a de novo mutation). Four cases showed a mild reduction in vital capacity, repeated nocturnal polysomnography showed hypoxaemia in one case. A variety of muscle biopsy features were found; central cores were absent in the youngest case, and the biopsy specimens from two others were more suggestive of mini-core myopathy. In all cases missense mutations in exons 101, 102, and 103 of the RYR1 gene on were found. Future laboratory diagnosis of suspected cases and family members will be less invasive and more accurate with DNA analysis. Clinicians, especially paediatricians and orthopaedic surgeons, should be aware of this disorder because of the potential risk of MH.