Histiocytosis-Lymphadenopathy Plus Syndrome

A number sign (#) is used with this entry because of evidence that histiocytosis and lymphadenopathy with or without cutaneous, cardiac, and/or endocrine features, joint contractures, and/or deafness (histiocytosis-lymphadenopathy plus syndrome) is caused by homozygous or compound heterozygous mutation in the SLC29A3 gene (612373) on chromosome 10q22.

Description

The histiocytosis-lymphadenopathy plus syndrome comprises features of 4 histiocytic disorders previously thought to be distinct: Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML), H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID). FHC described an autosomal recessive disease involving joint deformities, sensorineural hearing loss, and subsequent development of generalized lymphadenopathy and swellings in the eyelids that contain histiocytes (summary by Morgan et al., 2010). SHML, or familial Rosai-Dorfman disease, was described as a rare cause of lymph node enlargement in children, consisting of chronic massive enlargement of cervical lymph nodes frequently accompanied by fever, leukocytosis, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal sites were involved in approximately 25% of patients, including salivary glands, orbit, eyelid, spleen, and testes. The involvement of retropharyngeal lymphoid tissue sometimes caused snoring and sleep apnea (summary by Kismet et al., 2005). H syndrome was characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism; hearing loss was also found in about half of patients, and many had short stature. PHID was characterized by predominantly antibody-negative insulin-dependent diabetes mellitus associated with pigmented hypertrichosis and variable occurrence of other features of H syndrome, with hepatosplenomegaly occurring in about half of patients (Cliffe et al., 2009). Bolze et al. (2012) noted that mutations in the SLC29A3 gene (612373) had been implicated in H syndrome, PHID, FHC, and SHML, and that some patients presented a combination of features from 2 or more of these syndromes, leading to the suggestion that these phenotypes should be grouped together as 'SLC29A3 disorder.' Bolze et al. (2012) suggested that the histologic features of the lesions seemed to be the most uniform phenotype in these patients. In addition, the immunophenotype of infiltrating cells in H syndrome patients was shown to be the same as that seen in patients with the familial form of Rosai-Dorfman disease, further supporting the relationship between these disorders (Avitan-Hersh et al., 2011; Colmenero et al., 2012).

Clinical Features

Familial forms of histiocytosis are rare (Cline, 1994). In a highly consanguineous family originating from Pakistan, Moynihan et al. (1998) observed a seemingly new form of histiocytosis associated with joint contractures and sensorineural deafness, which they designated 'Faisalabad histiocytosis.' The index patient presented at age 3 years with rubbery swellings in her eyelids. The lesions were shown to contain histiocytes with increased numbers of plasma cells and eosinophils. The proband displayed systemic symptoms, with failure to thrive and generalized lymphadenopathy but no enlargement of liver or spleen. At age 15 years, she had symptoms of dyspnea and stridor and was found to have fever, lymphadenopathy, proptosis, raised erythrocyte sedimentation rates, and hypergammaglobulinemia. There was diffuse infiltration of the nasal mucosa and respiratory tract with lipogranulomatous material. With radiotherapy to the larynx and trachea, together with systemic administration of cyclophosphamide and prednisolone, marked improvement occurred. At age 17 years, she was noted to have scant secondary sexual characteristics and ovarian failure. Another affected member of the family was born with foot deformities and was noted to be deaf at age 5 years. Swellings developed around the eyes at age 13 years, and he later developed progressive deformities of the hands. At age 50, he developed swelling in his throat which required surgery, and he also had surgery to reduce swelling of the nasal turbinates. At the age of 58 years, he was totally deaf, had a wide and thickened nose, thick ears, soft swelling under the left eye, flexion deformities of all fingers, and severely deformed feet.

Kismet et al. (2005) reported 3 Turkish brothers with sinus histiocytosis and massive lymphadenopathy (SHML). The proband was an 8-year-old boy who presented at 2 years of age with fever, bilateral cervical and submandibular lymph node enlargement, and hepatomegaly. He had an elevated white blood cell count, erythrocyte sedimentation rate (ESR), and immunoglobulins, especially IgG. Histopathologic examination of a resected cervical lymph node revealed filling of the sinuses with benign-appearing histiocytes, plasma cells, and lymphocytes, causing marked dilation of sinuses and effacement of lymph node architecture by extensive histiocytosis. He also had severe sensorineural hearing loss. At age 8, interferon therapy resulted in regression of cervical lymph nodes and disappearance of sleep apnea. Two younger brothers were also affected, 1 displaying massive bilateral cervical and submandibular lymphadenopathy and fever, and the other presenting with an orbital mass, the histopathologic findings of which were consistent with SHML; the latter brother also had severe sensorineural hearing loss.

Marina and Broshtilova (2006) reported a 17-year-old Bulgarian boy with insulin-dependent diabetes mellitus (IDDM; 222100), growth retardation, and a 7-year history of skin changes consisting of induration, hyperpigmentation, and hypertrichosis on the anterior aspect of both thighs, lower abdomen, and scrotum. He also had scrotal edema, hypogonadism, gynecomastia, edema of the left leg, and hepatomegaly. Laboratory findings included hypothyroidism and decreased testosterone levels. There was thickening of the cardiac septum on echocardiogram. Light microscopy examination of a biopsy from affected skin revealed hyperkeratosis, acanthosis, increased pigmentation of the basal layer, a hypertrophic dermis with an accelerated fibroblast reaction, and a mild perivascular round-cell infiltrate. Marina and Broshtilova (2006) suggested that this combination of features represented incomplete POEMS syndrome (see 192240), noting that their patient did not have M-protein or polyneuropathy. Molho-Pessach et al. (2008) reexamined this patient at age 23 years and observed additional H syndrome-characteristic features, including facial telangiectases, mild proptosis, and bilateral camptodactyly.

In a 13-year-old girl and her 11-year-old brother, born of first-cousin parents, Hamadah and Banka (2006) described well-demarcated, nontender, hyperpigmented induration over the inner aspects of both thighs, extending to the pubic area and to the knees, with mild hypertrichosis over the thigh plaques. The lesions were slowly progressive over 2 to 5 years. The girl had mild labial swelling and the boy had diffuse pigmentation and induration of the scrotum with a swollen and retracted penis. Both had marked induration and atrophy of the lateral buttocks, resulting in a scalloped appearance bilaterally. Laboratory evaluation revealed elevated ESR and antinuclear antibody (ANA) levels in both sibs. Skin biopsy from both sibs was similar and showed plasma cell panniculitis, with an intense plasma cell and lymphocytic infiltrate and fibrosis primarily in the lower dermis and fat septae. A muscle biopsy from the boy was normal.

Rossbach et al. (2006) described 2 brothers, born to double first-cousin parents of Palestinian origin, who had lymphadenopathy, lymph node histology, and polyclonal hypergammaglobulinemia that was suggestive of Rosai-Dorfman disease (RDD), but who also displayed features reminiscent of the autosomal recessive syndrome referred to as Faisalabad histiocytosis, including intrauterine fractures, short stature, and sensorineural hearing impairment. The proband was born with intrauterine fractures of both humeri, the right femur, and the left fibula, as well as blue sclerae and low-set posteriorly rotated ears. At age 14 months, a CT scan of the brain due to developmental delay and generalized hypotonia revealed ventriculomegaly with communicating hydrocephalus and right lambdoid suture stenosis with subsequent plagiocephaly. Lymph node biopsy at age 17 months for chronic generalized lymphadenopathy was consistent with RDD, showing nodal capsular fibrosis and chronic inflammation, with distention of sinuses causing architectural distortion and partial effacement of follicles and germinal centers. Immunologic evaluation revealed elevated IgG and IgA. At age 16 years, he had short stature, severe sensorineural hearing impairment, a double-swirled hair pattern, frontal bossing, hypertelorism, pectus carinatum, and hyperpigmentation of his lower extremities. He had cervical, submandibular, and, most prominently, bilateral inguinal lymphadenopathy with confluence across the suprapubic area. A younger brother of the proband was also born with intrauterine fractures; studies in skin fibroblasts were normal. The postnatal period was complicated by patent ductus arteriosus, a small atrial septal defect, aspiration pneumonia, and polycythemia. IgG and IgA levels were significantly elevated on 2 occasions. At age 9 years, he had short stature and profound anemia, reticulocytopenia, and mild splenomegaly. Bone marrow revealed a nonclonal myeloproliferative process with large numbers of cells of the monocyte and histiocyte lineage, consistent with RDD, as well as moderate myelofibrosis. Rossbach et al. (2006) concluded that the brothers represented a second family with Faisalabad histiocytosis.

Prendiville et al. (2007) reported 4 unrelated boys, 3 with insulin-dependent diabetes, who had progressive development of pigmented hypertrichotic skin of the upper inner thighs with variable involvement of the genitalia, trunk and limbs. Three of the boys had consanguineous parents. Two boys had episcleritis and orbital proptosis with similar facies and musculoskeletal abnormalities including clinodactyly, flat feet, and short stature. Hepatosplenomegaly was present in 3 of the boys; echocardiogram was performed in 2 patients and revealed pericardial thickening in one and a bicommisural aortic valve in the other. Three of the boys had elevated laboratory markers of inflammation (ESR, C-reactive protein, IgA). Biopsy specimens from the skin and orbit showed a chronic inflammatory cell infiltrate composed of polyclonal lymphocytes, histiocytes, and plasma cells.

Molho-Pessach et al. (2008) reported 10 patients (9 males and 1 female) from 6 unrelated consanguineous Arab families from a small region near Jerusalem who had progressive cutaneous thickening, hyperpigmentation, and hypertrichosis beginning on the inner thigh and spreading to involve the middle and lower parts of their bodies, with conspicuous sparing of the knees and buttocks. Seven of the 10 patients had splenomegaly or hepatosplenomegaly; 5 had short stature; 5 had cardiac anomalies, including atrial and ventricular septal defects, mitral valve prolapse, and cardiomegaly; 5 had hearing loss; 6 had dilated lateral scleral vessels and 4 had exophthalmos. Several of the male patients had subcutaneous firm masses within a massively swollen scrotal sac with apparent micropenis, and 3 had gynecomastia. Laboratory evaluation of 4 patients revealed a highly elevated ESR and normal glucose; hormonal evaluation of 6 patients revealed growth hormone deficiency and hypergonadotropic hypogonadism, with azoospermia in 3 patients. Cutaneous histopathologic examination showed hyperpigmentation of the basal layer with seborrheic keratosis-like acanthosis, histiocytic infiltration, and a perivascular mononuclear infiltrate with plasma cells and mast cells throughout the dermis and subcutaneous fat. Molho-Pessach et al. (2008) designated this constellation of symptoms the 'H syndrome,' for hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and, occasionally, hyperglycemia.

Molho-Pessach et al. (2008) examined 8 new patients (4 males and 4 females) from 4 Arab families from a small region near Jerusalem who had findings similar to those of their previously reported patients (Molho-Pessach et al., 2008); additional clinical features that were prominent in these patients included hallux valgus, with fixed flexion contractures of the toe joints and of the proximal interphalangeal joints of the fingers. The authors stated that the previously reported camptodactyly in 2 of their patients likely represented a milder form of contractures of the proximal interphalangeal joints. Reexamination of members of their previously studied families identified 2 more male patients, aged 18 and 22 years, in whom the only abnormalities were dilated lateral scleral vasculature and prominent gynecomastia, respectively. The oldest surviving patient was a 50-year-old woman who had short stature, marked skeletal changes of the hands and feet, and hypogonadism manifesting as delayed puberty and primary amenorrhea.

Hussain et al. (2009) described 2 sisters, born of first-cousin Pakistani parents, who had autoantibody-negative diabetes mellitus, severe pancreatic exocrine deficiency, hyperpigmentation, hypertrichosis, hepatosplenomegaly with lymphadenopathy, and persistently elevated inflammatory markers. Both sibs displayed short stature and mild dysmorphism, including epicanthal folds, ptosis, hypertelorism, low set and posteriorly rotated ears, widely spaced nipples, and lipoatrophy of buttocks. The younger sib, who was more severely affected, also had conductive hearing loss of 30 dB diagnosed at the most recent exam at 7.9 years of age. The older sib had delayed puberty, and was still prepubertal at 14.3 years of age. Their parents were healthy and there were 2 unaffected sibs. Hussain et al. (2009) noted similarities between these patients and those described by Prendiville et al. (2007), and although the latter did not have pancreatic exocrine insufficiency, Hussain et al. (2009) thought it likely that they all had the same condition.

Molho-Pessach et al. (2010) described 2 patients with H syndrome, a 13-year-old Spanish boy and a 20-year-old Arab man, who both had fixed flexion contractures of the proximal interphalangeal (PIP) joints of the fourth and/or fifth fingers. Laboratory findings in both patients included mild microcytic anemia, elevated ESR and C-reactive protein, normal glucose level and liver function tests, and no abnormal plasma proteins; imaging studies showed splenomegaly and/or hepatomegaly and lymphadenopathy. Skin biopsy revealed a dermal infiltrate consisting of lymphocytes, plasma cells, and CD68+ (153634) histiocytes, and dermal and subcutaneous fibrosis. Colmenero et al. (2012) studied biopsies of affected skin and enlarged lymph nodes from the Spanish boy originally reported by Molho-Pessach et al. (2010) and observed that both the skin and lymph nodes displayed histopathologic features characteristic of Rosai-Dorfman disease, with some histiocytic cells exhibiting emperipolesis. Immunohistochemically, the histiocytes were CD14+ (158120), CD68+, CD163+ (605545), and CD1A- (188370), and in some areas of the dermis and subcutaneous tissue, histiocyte aggregates expressed S100 protein (see 176940) in their cytoplasm. Noting that the histiocytes in this disorder display the immunophenotype characteristic of Rosai-Dorfman disease, and that patients with Faisalabad histiocytosis (familial Rosai-Dorfman disease) have features overlapping those of H syndrome, Colmenero et al. (2012) suggested that Faisalabad histiocytosis and H syndrome are in fact the same entity.

Spiegel et al. (2010) reported an Israeli Moslem Arab family in which 2 sisters and their nephew were affected. The 28-year-old sister had clinical features consistent with classic PHID, consisting of insulin-dependent diabetes mellitus that developed at 12 years of age and the onset of hyperpigmented hypertrichotic sclerodermatous skin lesions at 14 years of age. She also had flat facies, gingival hypertrophy, and mild brachydactyly. Laboratory evaluation showed elevated ESR and C-reactive protein, mild polyclonal gammopathy, and negative autoantibody panels. The 5-year-old nephew's features were consistent with H syndrome: severe sensorineural hearing loss diagnosed at 2.5 years of age, short stature, bilateral proptosis with mild facial coarsening, thickened dorsum of both feet with mild hyperpigmentation but without hypertrichosis, mild splenomegaly, normal serum glucose, increased ESR and CRP, and mildly elevated IgG and IgA. The 23-year-old sister had a more severe phenotype that combined diagnostic features of both syndromes. She was evaluated at 4 years of age for hepatosplenomegaly and dysmorphic features, including bilateral exophthalmos, hypertelorism, flat and broad nasal bridge, upturned nares, prominent maxilla, and gingival hypertrophy. In addition, she had short stature, relatively short and broad fingers, and camptodactlyly, and was noted to have well-demarcated areas of hyperpigmented hypertrichotic skin, primarily on the lower abdomen, genital area, arms, and legs, with sparing of the knees. Biopsy of affected skin revealed lymphocytic and histiocytic infiltration of the deep dermis and intensive septal fibrosis of the subcutaneous fat. She developed difficult-to-control IDDM at 9 years of age, and 1 year later was found to have bilateral sensorineural hearing loss requiring the use of hearing aids. In addition, she displayed features not previously described as part of H syndrome or PHID, including severe seronegative polyarthritis involving both large and small joints, which developed at 13 years of age, and hypogonadotropic hypogonadism, with normal thyroid and adrenal function and normal signal and size of the pituitary gland on MRI. Laboratory evaluation revealed elevated ESR and CRP, and nonspecific polyclonal hypergammaglobulinemia.

Jonard et al. (2012) reported a 17-year-old Moroccan girl, born of first-cousin parents, who presented with a single cervical node at age 12 years, biopsy of which revealed proliferation of histiocytes with destruction of the follicles, consistent with the massive sinus histiocytosis of Rosai-Dorfman disease. At 14 years of age, she was diagnosed with severe bilateral sensorineural hearing loss. Her skin and limbs were normal, she had normal neurologic and endocrine development, and echocardiogram and glucose levels were normal.

Bolze et al. (2012) described a brother and sister, born of consanguineous parents of Moroccan origin, who had nasal granulomatous histiocytosis and were originally reported by de Pontual et al. (2008) as rhinoscleroma patients. However, histologic review of nasal biopsy specimens and 1 skin nodule showed features typical of Rosai-Dorfman histiocytosis, with large S100 protein-positive histiocytes with lymphocyte emperipolesis. The 33-year-old brother developed insulin-dependent diabetes mellitus at age 5 years, and was also found to have exocrine pancreatic insufficiency at age 9. At age 12, he had mild contractures of the fingers and toes, and at age 14, developed nasal obstruction with infiltrates of the nose and right maxillary sinus. His sister presented with nasal obstruction and epistaxis at age 5 years, but at age 23 years, did not have IDDM or exocrine pancreatic deficiency. Both sibs required surgery to relieve the nasal obstruction, and both displayed chronic inflammation, with a high ESR and polyclonal hypergammaglobulinemia. Cardiac morphology and function were normal by echocardiography, there were no pigmented hypertrichotic skin lesions, and hearing and eye examinations were normal in both sibs, except for mild diabetic retinopathy in the brother.

Mapping

Molho-Pessach et al. (2008) performed haplotype analysis in 17 patients with H syndrome and 22 unaffected family members and identified a single region of homozygosity on chromosome 10q21.3-q22.1, shared by 5 patients from 4 families. A recombination event in 1 family narrowed the interval of linkage to a 1.53-Mb region flanked by markers D10S529 and D10S606.

Cliffe et al. (2009) performed homozygosity mapping in 5 families with pigmented hypertrichosis and insulin-dependent diabetes (PHID), 4 previously reported by Prendiville et al. (2007) and 1 reported by Hussain et al. (2009), and identified a single common 1.4-Mb interval of shared homozygosity on chromosome 10q22.1, between rs10509321 and rs1900515.

In a highly consanguineous Pakistani family segregating Faisalabad histiocytosis, Moynihan et al. (1998) mapped the disorder to chromosome 11q25. However, using high-density SNP arrays, Morgan et al. (2010) reinvestigated this family and excluded a locus at 11q25. Instead, they found the largest region of homozygosity on chromosome 10q22.1, between SNPs rs12411657 and rs10999804. The affected Palestinian brothers with Faisalabad histiocytosis originally reported by Rossbach et al. (2006) also demonstrated a homozygous region at 10q22.1, between rs10509322 and rs16931177, that partially overlapped the minimal region from the Pakistani family. Genotyping of all available family members from the 2 families using microsatellite markers D10S537 and D10S1432 confirmed linkage, with a maximum multipoint lod score of 4.79 at D10S1432. A common region of autozygosity narrowed the candidate region to approximately 1 Mb between rs10509322 and rs10999804.

Molecular Genetics

In 18 patients from 10 Arab families with H syndrome mapping to a 1.53-Mb region on chromosome 10, Molho-Pessach et al. (2008) identified homozygosity or compound heterozygosity for 2 missense mutations and a 1-bp deletion in the SLC29A3 gene (G427S, 612373.0001; G437R, 612373.0002; and 1045delC, 612373.0003). The mutations segregated with the disease in all families. They subsequently sequenced the SLC29A3 gene in the Bulgarian patient reported by Marina and Broshtilova (2006) and identified homozygosity for the G427S mutation. Analysis of 362 and 212 geographically and ethnically matched chromosomes identified 4 G427S heterozygotes and 2 G437R heterozygotes, indicating a 1% frequency of both diseased alleles in this population. None of the mutations were found in 60 chromosomes from individuals of Jewish origin or in 76 control chromosomes from individuals of European or Bulgarian origin.

Cliffe et al. (2009) analyzed positional candidate genes in 5 families of diverse ethnic origins with pigmented hypertrichosis and insulin-dependent diabetes (PHID) mapping to 10q22.1, including 4 families reported by Prendiville et al. (2007) and the Pakistani family reported by Hussain et al. (2009), and identified homozygosity for 5 different mutations in the SLC29A3 gene. The mutations segregated with disease within the families and were not found in more than 100 Lebanese and Pakistani control chromosomes. Cliffe et al. (2009) suggested that PHID and H syndrome are different allelic entities.

In affected members of a Pakistani family with Faisalabad histiocytosis mapping to chromosome 10q22.1, previously studied by Moynihan et al. (1998), Morgan et al. (2010) excluded mutations in the candidate genes PRF1 (170280) and UNC5B (607870), and identified homozygosity for a splice site mutation in the SLC29A3 gene (612373.0008). In the Palestinian brothers with Faisalabad histiocytosis originally reported by Rossbach et al. (2006), Morgan et al. (2010) identified homozygosity for a missense mutation in SLC29A3 (G437R; 612373.0002). In 3 Turkish brothers with sinus histiocytosis and massive lymphadenopathy (SHML), originally studied by Kismet et al. (2005), Morgan et al. (2010) identified compound heterozygosity for G437R and a 2-bp deletion in SLC29A3 (612373.0009). Noting the overlapping phenotypes associated with mutations in SLC29A3, including H syndrome and PHID, Morgan et al. (2010) proposed that these related disorders be viewed as manifestations of an 'SLC29A3 spectrum disorder.'

In a 13-year-old Spanish boy with H syndrome, Molho-Pessach et al. (2010) identified homozygosity for a missense mutation in the SLC29A3 gene (R363Q; 612373.0010). In a 20-year-old Arab man with H syndrome, they identified homozygosity for a different missense mutation at the same residue (R363W; 612373.0011). Molho-Pessach et al. (2010) noted that although Cliffe et al. (2009) described their patients as having a disorder that was allelic to H syndrome, the clinical manifestations were identical. Molho-Pessach et al. (2010) stated that distinguishing these disorders according to severity of flexion contractures or presence or absence of diabetes mellitus or deafness is artificial, and that differences in clinical presentation are only due to phenotypic variability.

In an Israeli Moslem Arab family in which a 28-year-old woman had PHID, her 5-year-old nephew had H syndrome, and her 23-year-old sister had a more severe phenotype combining features from both syndromes, as well as the additional features of severe seronegative polyarthritis and hypogonadotropic hypogonadism, Spiegel et al. (2010) identified mutations in the SLC29A3 gene: the sisters were compound heterozygous for the G427S and G437R mutations, whereas their nephew was homozygous for the G437R mutation. Spiegel et al. (2010) concluded that PHID is not a distinct condition, but a milder form of SLC29A3-associated defects, and suggested that other factors are relevant to disease manifestations and severity.

In a 4-year-old girl, born of second-cousin parents of Arab origin, who had features consistent with H syndrome, including edematous and slightly indurated, hyperpigmented, and hypertrichotic skin over her buttocks and legs with sparing of the knees, and indurated, hyperpigmented but not hypertrichotic skin over her abdomen, Avitan-Hersh et al. (2011) identified homozygosity for a 1-bp deletion in the SLC29A3 gene (1045delC; 612373.0003). The patient also displayed short stature, exophthalmos, hepatosplenomegaly, and anemia, and was reported by her parents to have mild hearing loss. An additional finding was hydrocephalus, which the authors stated had not previously been described in H syndrome. She had an older brother with hepatospleomegaly, hearing loss, growth retardation, malabsorption with severe steatorrhea, and hydrocephalus, who died at 4 years of age due to complications of his cerebral shunt. Histochemical and immunohistochemical analysis of a biopsy from affected skin of the inner thigh of the proband revealed that the infiltrating mononuclear cells were CD68+, CD163+, S100+, and CD1a-, an immunophenotype that also characterizes the phagocytic cells present in Rosai-Dorfman disease.

In a 17-year-old Moroccan girl, born of first-cousin parents, who had sensorineural hearing loss and sinus histiocytosis limited to a single cervical node (SHML), Jonard et al. (2012) identified homozygosity for the R363Q mutation (612373.0010) in the SLC29A3 gene.

In 2 sibs from a consanguineous Moroccan family with nasal granulomatous histiocytosis, originally reported by de Pontual et al. (2008), Bolze et al. (2012) combined genomewide linkage analysis and whole-exome sequencing and identified a single pathologic variant in the chromosome 10 linkage region: a homozygous 1-bp deletion in the SLC29A3 gene (243delA; 612373.0012). Bolze et al. (2012) noted that the 243delA mutation results in the translation, expression, and function of an SLC29A3 isoform that is normally eliminated by nonsense-mediated decay. Bolze et al. (2012) concluded that this mechanism probably accounted for the sibs' narrow and mild clinical phenotype. The authors stated that mutations in SLC29A3 had been implicated in H syndrome, PHID, FHC, and SHML, with some patients presenting a combination of phenotypes from 2 or more of these syndromes, leading to the suggestion that these phenotypes should be grouped together as 'SLC29A3 disorder.' Bolze et al. (2012) noted that the histologic features of the lesions seemed to be the most uniform phenotype in these patients.

Campeau et al. (2012) described 2 patients with mutations in the SLC29A3 gene, in homozygous (612373.0007) or compound heterozygous (612373.0013-612373.0014) state, who presented with fractures, cortical thickening and widening of the diaphyses of the long bones, cranial base sclerosis, broad ribs with sclerosis, and platyspondyly. Patient 1 had recurrent ear and skin infections between the ages of 8 and 11 months. Patient 2 presented with a pulmonary infection at age 2 years and later required surgical removal of her adenoids for breathing difficulties. Although Campeau et al. (2012) suggested that these patients had dysosteosclerosis (224300), bone marrow biopsies were not performed in either child and their phenotype was milder than that in previously described dysosteosclerosis patients. Specifically, neither child had neurologic symptoms nor dental anomalies. Only patient 1 had skin findings, which were recurrent transient erythematous papules on the lower abdomen. Dual-energy x-ray absorptiometry for patient 1 showed a lumbar spine BMD Z-score of +8.1 at age 2 years and +11.9 at age 5. Moreover, the homozygous mutation (T449R; 612373.0007) in patient 2 had previously been identified in a patient with PHID (Cliffe et al., 2009) and one of the compound heterozygous mutations (R386Q; 612373.0013) in patient 1 had previously been identified in homozygous state in a patient with H syndrome (Farooq et al., 2012). For these reasons, the phenotype in the patients reported by Campeau et al. (2012) is currently cataloged in OMIM as histiocytosis-lymphadenopathy plus syndrome. Campeau et al. (2012) suggested that modifier genes may explain the pleiotropism and variability of SLC29A3-related diseases. Campeau et al. (2012) performed immunohistochemistry in mouse bone and showed expression of Slc29a3 in mouse osteoclasts in vivo. In peripheral blood monocytes from 2 dysosteosclerosis patients, they also demonstrated reduced osteoclast differentiation and reduced ability of the differentiated osteoclasts to demineralize a crystalline calcium phosphate surface.