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We report on a three generation family with four affected members presenting with a combination of B cell immunodeficiency, distal limbs abnormalities, genitourinary malformations, and mild dysmorphic features. All affected patients had normal intelligence and growth. No chromosomal abnormalities were observed using both standard and high resolution banding methods on the patients' lymphocytes. The observation of affected subjects of both sexes along with the occurrence of one male to male transmission suggests autosomal dominant inheritance of the trait with marked intrafamilial variable expression of the disease. While several multiple congenital anomalies (MCA) syndromes include both skeletal dysplasia and immune deficiency, the striking combination of congenital anomalies presented here, for which we propose the acronym BILU (B cell Immunodeficiency, Limb anomalies, and Urogenital malformations), is likely to represent a novel MCA syndrome.
The proband (case 1, IV.1, fig 1) is an only child, born to unrelated parents. He was born at term by caesarian section with normal measurements (weight 3620 g, length 50 cm, and OFC 37 cm). Genital anomalies noted at birth included micropenis, scrotal hypospadias, and bilateral cryptorchidism, which required multiple surgical corrections. Despite testosterone substitution therapy, the size of the testes and penis only increased during puberty. Endocrine investigations including basal state testosterone, dihydrotestosterone, adrenal hormones, gonadotrophin plasma levels, gonadotrophin response to LHRH, and testosterone response to HCG were normal. Ultrasonography of the urinary system showed bilateral hydronephrosis.
Urography (IV) showed right hydronephrosis with atresia of the upper segment of the right ureter, right vesicoureteral reflux, and absence of secretion in the left kidney (fig 2). A left ureteronephrectomy was performed at 2½ months. Histological examination of the left urinary apparatus showed a dysplastic kidney with segmental cortical agenesis and localised ureteral atresia with a very thin underlying ureter. Atresia of the right ureter also required surgical correction.
As shown in fig 3, the proband also had bilateral distal limb abnormalities including short digits, thenar hypoplasia, bilateral palmar creases, brachymesophalangism of both fifth fingers, congenital flexion contractures of the interphalangeal joints of both thumbs and both big toes, skin syndactyly of toes 3-4, and clinodactyly of the fourth toes. X rays showed bilateral brachymesophalangism of toes 3-5 and short articular distances between phalanges P1 and P2 of the fourth toes. Mild dysmorphic features were noted including mild hypertelorism and fullness of the periorbital regions (fig 1).
A history of respiratory infections led us to investigate the haematological and immunological status of the proband. He had marked hypogammaglobulinaemia involving at least IgG and IgA (table 1). Anti-polio virus antibodies I, II, and III and anti-B allohaemagglutinins were undetectable in the plasma. No CD19 and no surface IgM could be detected in blood, indicating the absence of B cells. In contrast, other blood cell counts were repeatedly normal, as were T cell numbers when expressed as absolute values or ratios (CD3=85%, CD4=45%, CD8=35% (proband aged 13 months)) and T cell functions (PHA, candidin, and tetanus toxoid proliferation assays, mixed leucocyte reaction, natural killer (NK) activity, and cell mediated cytotoxicity). There has been no significant immunological change in the course of the proband's life. He still has marked hypogammaglobulinaemia involving IgG, IgA, IgM, and IgG 1-3 subclasses (data not shown). Immunoglobulin perfusions were required every three weeks with a very good effect on respiratory infections. Unfortunately, we have not been able to perform a bone marrow biopsy as the proband has refused it so far, thus preventing the study of B lymphocyte precursors.
The proband had normal intelligence and growth until the age of 6 years when increased weight gain led to obesity (weight 113 kg, height 166 cm aged 15 years) and triggered or worsened psychological problems. Standard and high resolution banding karyotypes showed normal lymphocyte chromosomes.
The proband's father (case 2, III.2, fig 1) had recurrent episodes of respiratory infections, and had Streptoccocus pneumoniae meningitis at the age of 22, which led to investigation of his immune status (table 1). He had dissociated hypogammaglobulinaemia involving mainly IgG, IgA, and IgM with IgG1, IgG2, and IgG4 deficiency. Very few B cell lymphocytes could be detected using a CD19 specific antibody. He had normal T cell lymphocyte counts and functions. IV immunoglobulin substitution was initiated.
Fig 4 shows distal limb abnormalities including bilateral flexion contractures of the interphalangeal joints of the thumbs, hypoplasia of the thumbs, overlapping first and second toes, and skin syndactyly of toes 3-4. X rays showed brachymesophalangism of toes 2-5 with only two phalanges on the fifth toes and short metacarpophalangeal and interphalangeal articular distances of fingers (not shown). He had epispadias and his son (case 1) was born using artificial insemination.
Dysmorphic features consisted of mild hypertelorism (interpupillary distance of 6.5 cm), deep periorbital ridges, fullness of periorbital regions, mandibular hypoplasia, and a thin chin (fig 1). He had severe, non-progressive, bilateral, sensorineural deafness considered to be a consequence of his meningitis. Intelligence, height, and weight were normal. Standard chromosome studies on blood lymphocytes showed no anomalies.
The proband's paternal uncle (case 3, III.4, fig 1) had a similar disease history to his brother (case 2) with recurrent respiratory infections and a Streptoccocus pneumoniaemeningitis. He had dissociated hypogammaglobulinaemia with marked deficiency of IgG, IgA, and IgM and IgG1, IgG2, and IgG4 subclasses. No B cell lymphocytes could be detected (table 1). Bilateral symphalangism of the thumbs, epispadias which required surgical correction, and hypertelorism were noted. He had bilateral deafness considered to result from his meningitis, but which was not further investigated. He died from post-hepatitis cirrhosis. His blood karyotype performed using standard methods showed normal chromosomes.
The paternal grandmother of the proband (case 4, II.2, fig 1) had a humoral immune deficiency with slight IgG, IgG1, and IgG4 deficiencies but no detectable B cell lymphocytes (table 1) and normal T cell lymphocyte numbers and functions (lymphocyte proliferation after exposure to PHA). She had bilateral contractures of the interphalangeal joints of the thumbs and symphalangism of the thumbs as shown byx rays (fig 5), but no urogenital anomalies. Her parents were known to be healthy and her father was 38 years old at the time of her conception.
Here, we report on a striking combination of congenital anomalies, including B cell immunodeficiency, distal limb malformations, urogenital anomalies, and mild dysmorphic features in four members of a single three generation family. We propose the acronym BILU (B cell Immunodeficiency, Limb anomalies, and Urogenital malformations) as a means to make this association of signs easier to remember. Two of the four affected subjects (cases 2 and 3) also had deafness and one was obese (the proband, case 1). However, deafness started after aStreptococcus pneumoniae meningitis in both cases and the type of deafness was sensorineural and non-progressive in case 2 (not studied in case 3), suggesting that this feature may not be part of the BILU syndrome. Also, obesity in case 1 was associated with a unfavourable psychosocial status and, in our opinion, should not be considered as a specific sign. The occurrence of one male to male transmission together with the intrafamilial variability in phenotypic expression of the disease suggests autosomal dominant inheritance of the trait. Alternatively, an infracytogenetic chromosomal rearrangement might be responsible for the disease phenotype. However, the latter hypothesis is unlikely since neither mental retardation nor growth delay was observed in the affected subjects. This combination of congenital anomalies including B cell immunodeficiency appears unique and thus may represent an as yet undescribed autosomal dominant MCA syndrome.
Several short limbed dwarfisms/skeletal dysplasias (SLSD) have been found to be associated with immunodeficiency.1 Ammannet al 2 proposed a classification based on the immune defect. Type 1 includes early lethal SLSD with combined humoral (B cell) and cell mediated (T cell) immunodeficiency. Patients with type 1 SLSD appear to form a heterogeneous group.3 Some have adenosine deaminase (ADA) deficiency.3 4 Several reports have described type 1 SLSD cases associated with features of Ommen syndrome, namely eosinophilia, reticuloendotheliosis, alopecia, and ichthyosiform skin lesions.3 5-7 Type 2, less common than type 1, includes SLSD and T cell immunodeficiency, an association reminiscent of the cartilage-hair hypoplasia syndrome (CHH, MIM 250250), a metaphyseal dysplasia with short stature, fine and sparse blond hair, chronic neutropenia, and abnormal cellular immunity.8 9 This autosomal recessive condition has been mapped to chromosome 9p13.10 Type 3 (two sibs reported by Ammannet al 2) comprises SLSD with antibody mediated (B cell) immunodeficiency. It should be noted that skeletal phenotypes overlap considerably between these categories, apart from CHH which appears to be a genetically homogeneous condition. It is questionable whether this classification is relevant with regard to the underlying molecular pathology.
In the family presented here, the diagnosis of SLSD can easily be excluded since the patients do not have short stature. Moreover, urogenital anomalies are not commonly observed in SLSD. The pattern of congenital anomalies reported here shows some overlap with that of a 6 year old boy born to first cousin parents of Turkish origin described by Braegger et al.11 This patient had panhypogammaglobulinaemia, hypospadias, bilateral cryptorchidism, and distal limb anomalies comprising short hands and digits, short middle phalanges of the fifth fingers, and mild skin syndactyly of the toes. However, we believe that we are dealing with a different condition since this boy also displayed mental retardation, ischiadic hypoplasia, renal dysfunction without any obstructive uropathy, and marked facial dysmorphism. He had neither symphalangism nor limitation of flexion of the thumbs.
We will briefly describe other immuno-osseous syndromes with short stature. Each of these conditions also appears to be different from the BILU syndrome. Schimke immuno-osseous dysplasia (MIM 242900) includes short trunk skeletal dysplasia, glomerulonephritis with immune complex formation, and a defect of T cell maturation.12 13Ainsworth et al 14 reported a syndrome of selective IgG2 deficiency with severe growth retardation of prenatal onset, developmental delay, distal limb hypotrophy, dental anomalies, and eczematous skin.14 The Say-Barber-Miller syndrome includes B cell deficiency, short stature, hypoplastic patellae, multiple joint anomalies, microcephaly, mental retardation, hypogonadism, and unusual facies.15 16 Two female sibs with hypogammaglobulinaemia, multiple epiphyseal dysplasia, prenatal growth deficiency, microcephaly, mental retardation, cataracts, enamel hypoplasia, and downward slanting palpebral fissures were reported by Toriello et al.17 Unique combinations of immunodeficiency and skeletal dysplasia, such as those reported by Lichtenstein et al,18 Castriota-Scanderbeg et al,19 and Kultursay et al,20 should also be mentioned. Rare disorders such as Shokeir syndrome (MIM 274190) combine B cell deficiency and/or immunoglobulin abnormalities and a radial ray defect.21 22 Brewer et al 23 reported a male infant with low immunoglobulin values and bilateral radial aplasia, but this child also had anomalies absent in our patients, namely severe prenatal and postnatal growth retardation and markedly increased spontaneous chromosome breaks in leucocytes. This latter case may be related to the group of autosomal recessive chromosome breakage disorders including Fanconi anaemia. Finally, associations of B cell deficiency with alopecia, but without osseous anomalies, have also been reported by Ippet al.24
Careful examination of the skeletal and urogenital systems in patients with B cell immunodeficiency may hopefully lead to the identification of other cases similar to those observed in the family described here. The diagnostic importance of two rare signs observed in the family presented here, namely epispadias (cases 2 and 3) and symphalangism (cases 3 and 4), is worth noting. Each of these two signs may suggest the diagnosis of BILU syndrome when associated with B cell immunodeficiency. Finally, this observation raises the question of which gene(s) might be involved in three different developmental fields, such as the immune, skeletal, and urogenital systems.
We thank Mrs A Reumert-Kazès for her help with writing this manuscript.