Adducted thumbs: a clinical clue to genetic diagnosis.

Adducted thumbs are an uncommon congenital malformation. It can be an important clinical clue in genetic syndromes, e.g. the L1 syndrome. A retrospective survey was performed including patients with adducted thumbs referred to the Department of Clinical Genetics between 1985 and 2011 by perinatologists, (child) neurologists or paediatricians, in order to evaluate current knowledge on the genetic etiology of adducted thumbs. Twenty-five patients were included in this survey. Additional features were observed in 88% (22/25). In 25% (4/16) of the patients with adducted thumbs and congenital hydrocephalus L1CAM gene mutations were identified. One patient had a mosaic 5p13 duplication. Recommendations are made concerning the evaluation and genetic workup of patients with adducted thumbs.

Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.

The Ehlers-Danlos syndromes (EDS) form a clinically and genetically heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, tissue fragility and skin abnormalities. Six subtypes have been well characterized based on clinical features and molecular genetic abnormalities. The arthrochalasia type EDS (formerly types VIIA and B) is characterized by severe generalized joint hypermobility with multiple dislocations including congenital bilateral dislocation of the hips, muscular hypotonia and distinct dysmorphic features. The diagnosis of the arthrochalasia type EDS is of importance in the neonatal period because of consequences of physical disability in later life. However, the differential diagnosis may be difficult because of overlap with other hypermobility syndromes. In addition, the significant hypotonia may direct the physician toward various neuromuscular diagnoses. As patients become older, the hypotonia decreases and facial features become less distinct. In this report, we describe seven patients at different ages. Timing of diagnosis varied from prenatal life to adult age. The diagnosis of EDS type VII was confirmed by biochemical studies or mutation analysis showing characteristic mutations in COL1A1 and COL1A2. These mutations result in skipping of exon 6, which leads to defective collagen synthesis. For physicians treating patients with EDS type VII, achieving mobility for the patient is the greatest challenge and it may be impossible because of recurrent dislocations of nearly all joints in severe cases.

Unique skin changes in a case of Albright hereditary osteodystrophy caused by a rare GNAS1 mutation.

Albright hereditary osteodystrophy (AHO) is a syndrome of short stature, obesity, brachydactyly and subcutaneous calcifications with pseudohypoparathyroidism (PHP; leading to hypocalcaemia, hyperphosphataemia and elevated levels of parathyroid hormone, PTH). It was first described over 60 years ago. Since then, much has been learned about the aetiology of AHO which has been shown to be caused by heterozygous loss-of-function mutations within the GNAS1 gene. GNAS1 is subject to imprinting leading to phenotypic heterogeneity within kindreds with one mutation. Patients with AHO often present with symptoms of hypocalcaemia and/or with subcutaneous calcifications. The latter is thought to be the typical skin abnormality in AHO. We describe a family with AHO and hormone resistance (PHP type Ia) resulting from a rare mutation in GNAS1. The proband presented with small subcutaneous calcifications in the helix of the right ear and concentrated in a sharply demarcated zone of subcutaneous and dermal hypoplasia. This abnormality has so far not been described in patients with AHO. We speculate on the mechanism of dermal hypoplasia and resistance to PTH and suggest that subcutanous or dermal hypoplasia might be another feature which can be present in patients with AHO.

Trisomy 7p: report of 2 patients and literature review.

Two patients with a trisomy 7p are reported. Both were assessed by facial dysmorphism and congenital anomalies. In one of the patients trisomy 7p was a de novo event, in the other patient unbalanced inheritance of a parental translocation caused trisomy 7p. Developmental delay was severe in both. Our 2 cases are compared with patients reported in literature.

Two sibs with an unusual pattern of skeletal malformations resembling osteogenesis imperfecta: a new type of skeletal dysplasia?

We report a 6 year old boy with multiple fractures owing to bilateral, peculiar, wave-like defects of the tibial corticalis with alternative hyperostosis and thinning. Furthermore, he had Wormian bones of the skull, dentinogenesis imperfecta, and a distinct facial phenotype with hypertelorism and periorbital fullness. Collagen studies showed normal results. His sister, aged 2 years, showed the same facial phenotype and dental abnormalities as well as Wormian bones, but no radiographical abnormalities of the tubular bones so far. The mother also had dentine abnormalities but no skeletal abnormalities on x ray. This entity is probably the same as that described in a sporadic case by Suarez and Stickler in 1974. In spite of the considerable overlap with osteogenesis imperfecta (bone fragility, Wormian bones, and dentinogenesis imperfecta), we believe this disorder to be a different entity, in particular because of the unique cortical defects, missing osteopenia, and normal results of collagen studies.

Otoacoustic emissions in screening cleft lip and/or palate children for hearing loss--a feasibility study.

Patients with cleft lip and/or palate abnormalities are likely to suffer permanent conductive (PCHL) or sensorineural hearing loss (SNHL) due in part to the association with syndromes known to include PCHL or SNHL. The presence of otitis media, a nearly universal complication in these patients, makes identifying the hearing impaired in this population a challenge, since the detection of permanent hearing loss is made more difficult. This problem might be overcome by using click-evoked otoacoustic emissions (CEOAE's) shortly after birth. Twenty-one out of 28 newborns presented to the regional cleft palate team were eligible for CEOAE screening shortly after birth. Among these 21 infants, five had anomalies other than cleft lip and/or palate associated with an increased risk for hearing impairment. At the first CEOAE screening (ILO88 Emission Analyser, mean age 3 weeks, range 1-11 weeks) clear CEOAE's were present in all of the 18 ears of nine infants with isolated lip and/or jaw clefts. In 24 ears of 12 infants with palatal clefts, CEOAE's were present in only six ears (three infants), not demonstrable due to noisy registration in another six ears and absent in 12 ears despite a quiet registration. During follow-up of those who failed the first screening (18 ears, nine infants), normal hearing was found in 14 ears (seven infants) and sensorineural hearing loss was documented in four ears (two infants). CEOAE screening in infants with isolated lip and/or jaw clefts seems feasible and effective. In infants with palatal clefts an auditory brain stem screening might be more appropriate.

Does food intolerance play a role in juvenile chronic arthritis?

Sixty children with juvenile chronic arthritis (JCA) have been examined at the paediatric rheumatology out-patient clinic in Maastricht, of whom three ultimately appeared to have a food intolerance. In one of these three patients, there appeared to be a relationship with joint complaints. In the course of the elimination/challenge tests which were conducted, severe painful swelling of the knee occurred rapidly after each challenge. Three challenges were carried out with the same result each time. Since the symptoms did not disappear entirely following elimination of milk, it was concluded that milk intolerance in this case was an aggravating factor in a seronegative monoarticular JCA. In the second and third patients, a strict diet had no positive effect on the joint problems. In conclusion, the existence of such a connection between food and chronic joint complaints has been made clear, it only plays a role in incidental cases.

Severe feeding problems and congenital laryngostenosis in a patient with 3q23 deletion.

UNLABELLED: Common clinical features of patients with 3q23 deletion include the phenotype of BPES (blepharophimosis, ptosis, epicanthus inversus and telecanthus syndrome), growth and mental retardation, microcephaly ear and nose dysmorphism and joint and digit abnormalities. We report on a 3-year-old girl with the phenotype of BPES, mental retardation, facial dysmorphism and camptodactyly. In addition, she had a congenitally small larynx and severe, chronic feeding difficulties. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q23-q25). CONCLUSION: Congenital laryngostenosis and severe feeding problems may be part of the clinical syndrome caused by chromosome 3q23 deletion.

Deletion of the long arm of chromosome 6: two new patients and literature review.

Two children with a partial monosomy 6q are reported: a girl with an interstitial deletion [46,XX,del(6)(q16.2q23.1)], and a boy with a terminal deletion [46,XY,del(6)(q25.1)]. Both children presented with developmental delay, facial dysmorphism and a cardiac defect. The patients have been studied using G banding and cosmid probes specific for the long arm of chromosome 6. Clinical data are compared with patients reported in the literature.

Cow's milk protein intolerance in infants under 1 year of age: a prospective epidemiological study.

Incidence and clinical manifestation of cow's milk protein intolerance (CMPI) were studied in 1158 unselected newborn infants followed prospectively from birth to 1 year of age. No food changes were required in 914 infants who were used as healthy controls. When CMPI was suspected (211 infants), diagnostic dietary interventions according to a standard protocol were performed. After exclusion of lactose intolerance, two positive cow's milk elimination/challenge tests were considered diagnostic of CMPI. Two hundred and eleven symptomatic infants were examined for possible CMPI. A large group of 80 infants improved on a lactose reduced formula. In 87/211 infants CMPI was excluded (sick controls). Finally CMPI was proven in 26 infants. The calculated incidence rate for CMPI was 2.8%. The principal symptoms in infants with CMPI were gastrointestinal, dermatological and respiratory in 50%, 31% and 19% respectively. A positive family history for atopy (first or second degree relatives) was more frequent in either CMPI infants (65%), or sick controls (63%) when compared to either healthy controls (35%) or infants improving on a low lactose formula (51%). Differences between patients with CMPI and sick controls were only found for the presence of atopy in at least 2 first degree relatives [(5/26 in CMPI infants and 4/87 in sick controls (P < 0.05)] and for multiorgan involvement [10/26 infants with CMPI as opposed to 12/87 in the sick control group (P < 0.02)]. These statistical differences are too weak to be of clinical value.

Small intestinal mucosa IgE plasma cells and specific anti-cow milk IgE in children with cow milk protein intolerance.

In a prospective study we looked for the presence of both IgE plasma cells in small bowel mucosa and specific serum IgE antibodies to cow milk in children suspected of cow milk protein intolerance. Thirty-one children with complaints possibly due to cow milk intolerance were submitted to two consecutive cow milk elimination/challenge tests. The diagnosis of cow milk protein intolerance was confirmed in 16 of our 31 patients on the basis of two positive elimination/challenge tests. IgE plasma cells were found in nine of 16 patients with proven cow milk protein intolerance and in only one of the 15 patients without cow milk protein intolerance (p < .01). The RAST for cow milk was positive in six of 16 infants with cow milk protein intolerance and in two of the 15 other infants. Serum IgE level was of no value for the diagnosis of cow milk protein intolerance. Neither of these diagnostic procedures was sensitive enough to be used as a screening test for cow milk protein intolerance. Furthermore, the relationship between specific IgE antibodies for cow milk and the presence of mucosal IgE plasma cells was poor: five of nine infants with cow milk protein intolerance and the presence of mucosal IgE plasma cells had negative RASTs for cow milk.

Follow up study of cow's milk protein intolerant infants.

Over a period of 4 years, 88 infants with cow's milk protein intolerance (CMPI) were followed prospectively in order to evaluate the persistence of CMPI and its relationship between either serum IgE levels or RAST results for cow's milk. After exclusion of lactose intolerance, two positive cow's milk elimination challenge tests were considered diagnostic for CMPI. At the age of 1, 2, 3 and 4 years respectively, 85%, 78%, 49% and 33% of the children still were cow's milk intolerant. Initial serum values of IgE greater than or equal to 10 kU/l indicated a late development of tolerance to cow's milk proteins. At the age of 4 years, 90% of infants with initial IgE levels less than 10 kU/l had become tolerant to cow's milk while this was the case for only 47% of infants with initial IgE levels greater than or equal to 10 kU/l. Initial RAST results for cow's milk bore no obvious relationship to outcome.

Distal arthrogryposis, specific facial dysmorphism and psychomotor retardation: a recognizable entity in surviving patients with the fetal akinesia deformation sequence.

Two non-related patients, a boy and a girl, are described suffering from distal arthrogryposis and facial dysmorphism consisting of flat face, hypertelorism and telecanthus, small mouth with thin, downturned upper lip, micrognathia, cleft palate and simple, low-set, posteriorly angulated ears. Feeble fetal movements (case 2), polyhydramnion (case 1) and lung hypoplasia (case 2) were present. On follow-up, both children were severely developmentally retarded. These findings are consistent with the Fetal A/hypokinesia Deformation Sequence (FADS). Survival beyond the neonatal period in this heterogeneous condition seems to be rare. Clinical descriptions of infants with FADS surviving the neonatal period are most important in order to delineate clinically recognizable entities; it may help to disclose pathogenetic basic mechanisms.

[Congenital cytomegalovirus infection]. / Congenitale cytomegalovirus-infectie.

Until recently, prevention and treatment of congenital cytomegalovirus infection was not possible. However, several studies on the epidemiology of congenital CMV infection and the development of vaccines, diagnostic tests and antiviral drugs such as ganciclovir may improve the perspectives for patients with congenital CMV disease. In this article we will discuss several of those developments that may offer new approaches for prevention and treatment of congenital CMV disease.

[51Cr]EDTA intestinal permeability in children with cow's milk intolerance.

Making use of [51Cr]EDTA as a permeability marker, we measured intestinal permeability in a group of 20 children with proven cow's milk intolerance (CMI), a group of 17 children with similar complaints where CMI was excluded (sick controls), and a group of 12 control children. [51Cr]EDTA test results (mean +/- SD) were 6.85 +/- 3.64%, 3.42 +/- 0.94%, and 2.61 +/- 0.67% in the group with CMI, the sick control, and the control group, respectively. When compared to both control groups, patients with cow's milk intolerance (CMI) showed a significantly increased small bowel permeability. We conclude that the [51Cr]EDTA test can be helpful for the diagnosis of cow's milk intolerance.