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1.  Familial Poland anomaly. 
Journal of Medical Genetics  1982;19(4):293-296.
The Poland anomaly is usually a non-genetic malformation syndrome. This paper reports two second cousins who both had a typical left sided Poland anomaly, and this constitutes the first recorded case of this condition affecting more than one member of a family. Despite this, for the purposes of genetic counselling, the Poland anomaly can be regarded as a sporadic condition with an extremely low recurrence risk.
PMCID: PMC1048897  PMID: 6288948
2.  Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome. 
Archives of Disease in Childhood  1993;68(4):453-457.
The partial androgen insensitivity syndrome occurs in 46,XY subjects with phenotypes ranging from perineoscrotal hypospadias with cryptorchidism and micropenis (mild undervirilisation) to clitoromegaly and partial labial fusion (marked undervirilisation). Within an affected family, wide variation in the degree of genital ambiguity between individuals can be seen. Two cousins of a previously reported subject who had severe genital ambiguity and partial androgen insensitivity were investigated. Neither of the cousins had genital abnormalities as marked as the index case, who also had qualitatively abnormal androgen binding and two mutations of the androgen receptor gene. Despite marked phenotypic differences between the index case and his cousins, similar androgen binding and the same androgen receptor mutations were shown in the cousins. Furthermore, one of the androgen receptor gene mutations has been shown in the mother and sister of one of the boys indicating that they are carriers. Thus phenotypic variation in families affected by partial androgen insensitivity is dependent on factors other than abnormalities of the androgen receptor gene alone. Although carrier status in partial androgen insensitivity can be determined, the severity of genital abnormalities in an affected offspring cannot be reliably predicted.
PMCID: PMC1029262  PMID: 8099270
3.  Discordant, non-syndromic, congenital diaphragmatic defects in sibs. 
Journal of Medical Genetics  1989;26(12):781-782.
We report an Arab sibship of two brothers with non-syndromic, congenital diaphragmatic defects (CDD). The first had an extensive, left, Bochdalek-type hernia and the second hemidiaphragmatic agenesis; these were verified by surgical exploration and necropsy respectively. The parents are healthy second cousins. Other reported discordant cases of CDD are briefly reviewed.
PMCID: PMC1015762  PMID: 2614799
4.  Cone-rod congenital amaurosis associated with congenital hypertrichosis: an autosomal recessive condition. 
Journal of Medical Genetics  1989;26(8):504-510.
Two female cousins were found to be affected with severe retinal dystrophy characterised by visual impairment from birth and profound photophobia in the absence of night blindness. Minimal fundus changes with a small foveal atrophy in the older cousin and slight macular pigment epithelial changes suggestive of early bull's eye appearance in the younger were detected, indicative of a cone-rod type of congenital amaurosis. This was associated with trichomegaly, bushy eyebrows with synophyrys, and excessive facial and body hair (including hypertrophied circumareolar hair on the breasts of the older cousin). The mode of inheritance appears to be autosomal recessive.
PMCID: PMC1015672  PMID: 2769722
5.  Bilateral absence of the kidneys and ureters. Three cases reported in one family. 
Journal of Medical Genetics  1977;14(3):205-209.
Three infant boys with bilateral absence of the kidneys and hypoplasia of the lungs are described. Two of the infants were brothers and the third was a first cousin. They were born to 2 sisters whose husbancs were unrelated to their wives and to each other. None of the parents had renal problems. The occurrence of this syndrome in 2 male sibs is suggestive of an autosomal recessive inheritance pattern which has been previously described. An additional male first cousin born to the mother's sister is sugesstive of sex-linked inheritance for this particular family, an inheritance pattern not previously described.
PMCID: PMC1013558  PMID: 881712
6.  Agenesis of the Corpus Callosum in Two Sisters 
Journal of Medical Genetics  1973;10(3):266-269.
Two sisters are described. They are offspring of Arabic parents who are both first and second cousins, through both sets of grandparents; additionally the father's parents are first cousins. The diagnosis of agenesis of the corpus callosum in the propositae was made by the characteristic picture on the pneumoencephalogram.
The clinical symptoms in the two sisters varied considerably. The older sister had shown delayed psychomotor development in infancy, mild mental retardation, and developed seizures at 7 years of age of both the grand mal and akinetic types. Her physical and neurological examination did not show any abnormalities. The EEG was severely abnormal with slow wave activity over the posterior parts of the brain and focal spiking. The younger sister presented at 6 months of age with failure to thrive, generalized hypotonia, but without seizures. Her EEG was within normal limits.
This anomaly was probably transmitted by an autosomal recessive gene. The clinical and genetic aspects of this syndrome are discussed.
PMCID: PMC1013031  PMID: 4204338
7.  Autosomal recessive sudden unexpected death in children probably caused by a cardiomyopathy associated with myopathy. 
Journal of Medical Genetics  1979;16(5):341-346.
The propositus, who died suddenly at the age of 22 months, was investigated because of an unusual myopathy. Family history revealed two sisters and four cousins who had also died suddenly and unexpectedly. The finding of asymmetric septal hypertrophy by echocardiography in the propositus suggested that the cause of the sudden death in the relatives was an undetected cardiomyopathy accompanying a mild and often subclinical myopathy. The affected children were in two sibships and both sets of parents were first cousins. The mother of one sibship was the sister of the father of the other. It is suggested that a gene causes a mild autosomal recessive myopathy with cardiomyopathy that is often undiagnosed and usually ends in sudden unexpected death in the second year of life. The same gene may manifest on echocardiogram in some heterozygotes as asymmetric septal hypertrophy.
PMCID: PMC1012606  PMID: 513079
8.  Absent left hemidiaphragm, arhinencephaly, and cardiac malformations. 
Journal of Medical Genetics  1978;15(5):399-401.
An infant is reported with absent left hemidiaphragm, hydrocephalus, arhinencephaly, and cardiovascular anomalies. The parents are second cousins.
PMCID: PMC1013741  PMID: 739533
9.  Association of syndactyly, ectodermal dysplasia, and cleft lip and palate: report of two sibs from Turkey. 
Journal of Medical Genetics  1988;25(1):37-40.
Two Turkish sibs, products of a second cousin marriage, with tetramelic syndactyly, ectodermal dysplasia, cleft lip and palate, renal anomalies, and mental retardation are reported. Similarities between these two brothers and previously reported cases and their mode of transmission are discussed.
PMCID: PMC1015420  PMID: 2832607
10.  Family occurrence of achalasia and diffuse spasm of the oesophagus. 
Gut  1988;29(11):1595-1602.
In view of the unknown aetiology of achalasia and diffuse oesophageal spasm we report four families (father/son, mother/son, brother/brother, cousin/cousin) with achalasia and oesophageal spasm examined by radiology, endoscopy and manometry. Family occurrence of oesophageal motor disorders supports the hypothesis that a genetic trait may play a role in the pathogenesis. The family coincidence of achalasia and oesophageal spasm supports a close relationship between the two diseases.
PMCID: PMC1433819  PMID: 3061886
11.  X linked alpha thalassaemia/mental retardation: spectrum of clinical features in three related males. 
Journal of Medical Genetics  1991;28(11):738-741.
We describe three males (two brothers and a cousin) who have the X linked alpha thalassaemia/mental retardation (ATR-X) syndrome. The diagnosis, originally suspected in the brothers because of similarity in dysmorphic features to previous cases, was confirmed haematologically in the surviving brother. The cousin has less typical dysmorphism and a virtually normal routine blood count, but haemoglobin H inclusions were found in his red blood cells showing that he has the same condition. This report expands the clinical phenotype of the ATR-X syndrome and emphasises that a normal blood count does not exclude the diagnosis.
PMCID: PMC1017107  PMID: 1770529
12.  Organisation of the human PAX4 gene and its exclusion as a candidate for the Wolcott-Rallison syndrome. 
Journal of Medical Genetics  1998;35(4):288-292.
Neonatal diabetes mellitus is a rare condition, the causes of which are mostly unknown. One well defined though very rare entity is the autosomal recessive Wolcott-Rallison syndrome, in which permanent neonatal diabetes, osteopenia, and epiphyseal dysplasia occur. Only five previous families have been reported, and here we describe the second in which parental consanguinity was present. The proband was born to first cousin parents and died at 2 years from the sequelae of poorly controlled diabetes. To test the hypothesis that mutation of PAX4, required in the mouse for pancreatic islet beta cell development, might cause WRS, the structure of the human PAX4 gene was deduced and DNA from two unrelated WRS patients sequenced. No PAX4 mutation was present, though the entire coding region was sequenced in both patients. It therefore appears unlikely that PAX4 is involved in the aetiology of Wolcott-Rallison syndrome, though it remains a good candidate for other forms of neonatal diabetes mellitus.
PMCID: PMC1051275  PMID: 9598721
13.  Paternal Robertsonian translocation t(13q;14q) and maternal reciprocal translocation t(7p;13q) in a couple with repeated fetal loss. 
Journal of Medical Genetics  1984;21(6):463-464.
Marriages involving partners both of whom have abnormal karyotypes are rare and are usually ascertained because of a history of infertility, repeated abortions, or the birth of a balanced translocation carrier or chromosomally abnormal offspring. Abnormalities which have been noted include sex chromosome aberrations in both parents or a sex chromosome abnormality in one parent and an autosomal abnormality in the other. Four papers have reported balanced reciprocal autosomal translocations in both parents, two couples representing a first cousin marriage. We present a case of a paternal 13;14 Robertsonian translocation and a maternal (7p;13q) reciprocal translocation in a couple with repeated fetal loss.
PMCID: PMC1049349  PMID: 6512837
14.  Nasopharyngeal carcinoma and Burkitt's lymphoma in a Canadian family. I. HLA typing, EBV antibodies and serum immunoglobulins. 
Two nasopharyngeal carcinomas of the lymphoepithelioma type and two Burkitt's lymphomas with the characteristic histopathologic features developed in three siblings and one first-degree cousin in a large French-Canadian family. Epstein-Barr virus antibody titres in the two lymphoepithelioma cases but not in the Burkitt's lymphoma cases were, as expected, greatly elevated. HLA typing of the family members failed to disclose HLA antigens A2 and B Sin-2, which have been associated with lymphoepithelioma in Asia. The occurrence, however, of a plasmacytoma in one other first-degree cousin and low serum IgA values in several siblings and cousins suggests the possibility of a genetically determined predisposing B-cell dysfunction in the development of these tumours.
PMCID: PMC1879112  PMID: 186168
15.  Familial autosomal recessive rigid spine syndrome with neurogenic facio-scapulo-peroneal muscle atrophy. 
Two sisters and a first cousin presented with rigid spine and facio-scapulo-peroneal muscle atrophy. The patients belonged to a family with two first-cousin marriages. Electromyography, muscle and nerve biopsy showed neurogenic muscle atrophy without peripheral nerve involvement. Follow up did not show progression of the disease. This is the first observation of an association of neurogenic facio-scapulo-peroneal and rigid spine syndrome. The double first-cousin marriage suggests autosomal recessive inheritance.
PMCID: PMC1014297  PMID: 2010758
16.  Absence/hypoplasia of tibia, polydactyly, retrocerebellar arachnoid cyst, and other anomalies: an autosomal recessive disorder. 
Journal of Medical Genetics  1995;32(11):896-900.
Absence or hypoplasia of the tibia has been reported to occur as an isolated hereditary malformation as well as a feature of several autosomal recessive and autosomal dominant syndromes. We report three sibs with absence or hypoplasia of the tibia in association with other malformations whose parents are first cousins once removed. These infants appear to have a "new" autosomal recessive syndrome.
PMCID: PMC1051745  PMID: 8592337
17.  Crossed avoiding reaction: a disturbance of the manual spatial function. 
A patient with MRI confirmed lesions in the corpus callosum and the left cingulate gyrus had a rare syndrome of crossed avoiding reaction of the left hand. With the right hand she could reach a stimulus object in whatever space it was presented. With the left hand, however, she could not mobilise it to reach a stimulus presented in the right hemispace relative to her body axis. In the left hemispace relative to her body axis her left hand reached an object without any difficulty. This left unilateral difficulty in the right unilateral space may be related to a unique spatial function that controls manual space, which is represented differentially in the two hemispheres. In the left hemisphere this function covers bilateral hemispace and is operated by the right hand. In the right hemisphere this function covers only the left hemispace and is operated by the left hand.
PMCID: PMC1015018  PMID: 8505650
18.  Two sibs with microcephaly, hygroma colli, renal dysplasia, and cutaneous syndactyly: a new lethal MCA syndrome? 
Journal of Medical Genetics  1999;36(6):481-484.
We report two sibs of Turkish descent with multiple congenital anomalies including severe microcephaly, hygroma colli, cystic renal dysplasia, and bilateral cutaneous syndactyly of toes IV-V. In addition, the second sib presented with bilateral fusion of the eyelids, a bicornuate uterus, and clitoromegaly. The parents are first cousins, which suggests autosomal recessive inheritance. In reviewing previously published reports, several cases were found with cerebral, renal, and digital anomalies as the main features. Several of the additional symptoms present in the second sib were suggestive of Fraser syndrome, but the severe microcephaly in both sibs is unusual. The differential diagnosis is discussed, including the possibility of an entirely new entity in the broad spectrum of syndromes with cerebral, renal, and digital anomalies.

Keywords: lethal MCA syndrome; microcephaly; cystic renal dysplasia; cutaneous syndactyly
PMCID: PMC1734377  PMID: 10874639
19.  Deletion of the fibrogen alpha-chain gene (FGA) causes congenital afibrogenemia 
Journal of Clinical Investigation  1999;103(2):215-218.
Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by the complete absence of detectable fibrinogen. Uncontrolled bleeding after birth from the umbilical cord is common, and spontaneous intracerebral bleeding and splenic rupture can occur throughout life. Patients respond well to fibrinogen replacement therapy, either prophylactically or on demand. Because the half-life of infused fibrinogen is essentially normal, the genetic defect is assumed to be at the level of synthesis, but no responsible locus has been identified. Preliminary studies using Southern blotting suggested that no gross structural changes of the fibrinogen genes were present in patients. We report the identification of causative mutations in a nonconsanguineous Swiss family with congenital afibrinogenemia. The four affected male individuals (two brothers and their two first cousins) have homozygous deletions of ∼11 kb of the fibrinogen alpha-chain gene (FGA). Haplotype data suggest that these deletions occurred separately, on three distinct ancestral chromosomes, implying that the FGA region of the fibrinogen locus is susceptible to deletion by a common mechanism. Furthermore, our results demonstrate that humans, like mice, may be born without the capacity to synthesize functional fibrinogen.
PMCID: PMC407887  PMID: 9916133
20.  Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome 
British Journal of Cancer  2007;98(2):474-479.
Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.
PMCID: PMC2361463  PMID: 18087273
paediatric brain tumour; rhabdoid tumour predisposition syndrome; INI1; germline mutation; penetrance
21.  Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome 
Journal of Medical Genetics  1999;36(9):700-704.
Classical neonatal diabetes mellitus is defined as hyperglycaemia occurring within the first six weeks of life in term infants. Cerebellar agenesis is rare. We report three cases of neonatal diabetes mellitus, cerebellar hypoplasia/agenesis, and dysmorphism occurring within a highly consanguineous family. This constellation of abnormalities has not previously been described. Two of these cases are sisters and the third case is a female first cousin. The pattern of inheritance suggests this is a previously undescribed autosomal recessive disorder. Prenatal diagnosis of the condition in this family was possible by demonstration of the absence of the cerebellum and severe IUGR.

Keywords: cerebellar agenesis/hypoplasia; neonatal diabetes mellitus; dysmorphic features; autosomal recessive
PMCID: PMC1734417  PMID: 10507728
22.  Two new families with hereditary minimal change disease 
BMC Nephrology  2013;14:65.
Steroid-sensitive idiopathic nephrotic syndrome (SSINS) is most often encountered in sporadic cases of minimal change disease (MCD). Only rare cases of familial forms of MCD have been reported and most of them only in one generation. The scarcity of data has precluded unraveling the underlying genetic defect and candidate gene approaches have been unsuccessful. Here we report two families with related SSINS cases and review the related literature.
Case presentation
Two siblings and a cousin (first family), and a father and his son (second family), are reported with SSINS due to MCD. Patients have been followed up for more than 12 years and a renal biopsy was performed in three cases, demonstrating typical features of MCD. The course of the disease was remarkable because of several relapses treated with steroids. In three cases, mycophenolate mofetil or cyclosporine was added.
Familial SSINS due to MCD is extremely rare and no genetic defect has been identified so far. Reporting cases of hereditary MCD will allow further genetic studies which will ultimately help unravel the molecular basis of this disease.
PMCID: PMC3616856  PMID: 23517548
Nephrotic syndrome; Minimal change disease; Heredity; Genetics; Steroids
23.  A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents. 
Journal of Medical Genetics  1993;30(6):470-475.
Leprechaunism is a rare autosomal recessive disorder associated with extreme insulin resistance with paradoxical hypo-glycaemia. It is characterised by prenatal and postnatal growth retardation, reduced subcutaneous tissue, coarse features, acanthosis nigricans, enlarged genitalia, and death in the first year of life. Defects in both the insulin receptor and postreceptor steps of the insulin action pathway have been reported. At the molecular level, several mutations have been described. The patients reported here are from a Yemeni family with a syndrome of insulin resistance similar to leprechaunism in which the parents are second cousins and five of their eight children are affected. However, the phenotypes seem to be less severe than the classical leprechaunism previously described. All the children are alive (oldest 11 years), there is normal subcutaneous tissue, and a normal growth pattern in some of them. It may be that this is a milder type of leprechaunism with a better prognosis, perhaps caused by a different type of mutation from those previously described.
PMCID: PMC1016418  PMID: 8326490
24.  Purine Nucleoside Phosphorylase Deficiency 
Journal of Clinical Investigation  1977;60(3):741-746.
Purine-nucleoside phosphorylase (NP) deficiency is associated with severely defective thymus-derived (T)-cell and normally functioning bone marrow-derived (B)-cell immunity. In this study, two unrelated families with a total of three NP deficient members were investigated.
High pressure liquid chromatography of the plasma of the three patients showed inosine levels greater than 66 μM. This nucleoside was absent from the plasma of their parents and control samples.
NP was purified from normal human erythrocytes by affinity chromatography and an antiserum prepared in rabbits was used to study the NP variants in the two families.
In family M the patient had no detectable erythrocyte NP activity and no detectable immunological-reacting material (irm) to the NP antibody. The parents, who are second cousins, had less than one-half of normal enzyme activity and approximately 14% irm attributable to a variant protein. Their electrophoretic patterns revealed a series of isozymes with slower than normal migration.
In family B the patients had 0.5% residual enzyme activity and about one-half normal irm. Their electrophoretic pattern showed faintly staining bands which migrated faster than normal NP. The mother of the patients had one-half normal enzyme activity, 11% irm attributable to her variant protein, and a normal electrophoretic pattern. The father had less than one-half normal enzyme activity, equal amounts of normal and variant irm, and an electrophoretic pattern that showed increased activity of the more rapidly migrating isozyme bands.
The combined use of immunological and electrophoretic techniques has shown the presence of three separate mutations; one in family M and two in family B associated with severely defective T-cell function.
PMCID: PMC372419  PMID: 408378
25.  Familial jejunal atresia with 'apple-peel' variant. 
We report two siblings who had jejunal atresia which we believe to be familial. The parents of these siblings were first cousins. The first child had jejunal atresia with mesenteric agenesis and 'apple-peel' configuration; the second child had jejunal atresia with a V-shaped mesenteric defect. Other reported cases of familial atresia of the small intestine are reviewed.
PMCID: PMC1439050  PMID: 7265073

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