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Spondyloenchondrodysplasia with immune dysregulation(SPENCDI)

MedGen UID:
375009
Concept ID:
C1842763
Disease or Syndrome
Synonyms: COMBINED IMMUNODEFICIENCY WITH AUTOIMMUNITY AND SPONDYLOMETAPHYSEAL DYSPLASIA; ROIFMAN IMMUNOSKELETAL SYNDROME; SPENCDI; SPONDYLOENCHONDRODYSPLASIA WITH OR WITHOUT IMMUNE DYSREGULATION
SNOMED CT: Roifman-Melamed syndrome (703523004); Combined immunodeficiency with autoimmunity and spondylometaphyseal dysplasia (703523004); Spondyloenchondrodysplasia with immune dysregulation (703523004); Roifman-Costa syndrome (703523004)
 
Gene (location): ACP5 (19p13.2)
 
Monarch Initiative: MONDO:0011939
OMIM®: 607944
Orphanet: ORPHA50816

Definition

Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (Menger et al., 1989). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (Renella et al., 2006). Briggs et al. (2016) also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family. Classification of the Enchondromatoses In their classification of the enchondromatoses, Spranger et al. (1978) called Ollier disease and Maffucci syndrome types I and II enchondromatosis, respectively; metachondromatosis (156250), type III; and spondyloenchondrodysplasia (SPENCD), also called spondyloenchondromatosis, type IV; enchondromatosis with irregular vertebral lesions, type V; and generalized enchondromatosis, type VI. Halal and Azouz (1991) added 3 tentative categories to the 6 in the classification of Spranger et al. (1978). Pansuriya et al. (2010) suggested a new classification of enchondromatosis (multiple enchondromas). [from OMIM]

Additional description

From MedlinePlus Genetics
Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an inherited condition that primarily affects bone growth and immune system function. The signs and symptoms of SPENCDI can become apparent anytime from infancy to adolescence.

Bone abnormalities in individuals with SPENCDI include flattened spinal bones (platyspondyly), abnormalities at the ends of long bones in the limbs (metaphyseal dysplasia), and areas of damage (lesions) on the long bones and spinal bones that can be seen on x-rays. Additional skeletal problems occur because of abnormalities of the tough, flexible tissue called cartilage that makes up much of the skeleton during early development. Individuals with SPENCDI often have areas where cartilage did not convert to bone. They may also have noncancerous growths of cartilage (enchondromas). The bone and cartilage problems contribute to short stature in people with SPENCDI.

Individuals with SPENCDI have a combination of immune system problems. Many affected individuals have malfunctioning immune systems that attack the body's own tissues and organs, which is known as an autoimmune reaction. The malfunctioning immune system can lead to a variety of disorders, such as a decrease in blood cells called platelets (thrombocytopenia), premature destruction of red blood cells (hemolytic anemia), an underactive thyroid gland (hypothyroidism), or chronic inflammatory disorders such as systemic lupus erythematosus or rheumatoid arthritis. In addition, affected individuals often have abnormal immune cells that cannot grow and divide in response to harmful invaders such as bacteria and viruses. As a result of this immune deficiency, these individuals have frequent fevers and recurrent respiratory infections.

Some people with SPENCDI have neurological problems such as abnormal muscle stiffness (spasticity), difficulty with coordinating movements (ataxia), and intellectual disability. They may also have abnormal deposits of calcium (calcification) in the brain.

Due to the range of immune system problems, people with SPENCDI typically have a shortened life expectancy, but figures vary widely.  https://medlineplus.gov/genetics/condition/spondyloenchondrodysplasia-with-immune-dysregulation

Clinical features

From HPO
Tubulointerstitial fibrosis
MedGen UID:
370652
Concept ID:
C1969372
Disease or Syndrome
A progressive detrimental connective tissue deposition (fibrosis) on the kidney parenchyma involving the tubules and interstitial tissue of the kidney. Tubulointerstitial injury in the kidney is complex, involving a number of independent and overlapping cellular and molecular pathways, with renal interstitial fibrosis and tubular atrophy (IF/TA) as the final common pathway. However, IF and TA are separable, as shown by the profound TA in renal artery stenosis, which characteristically has little or no fibrosis (or inflammation). For new annotations it is preferable to annotate to the specific HPO terms for Renal interstitial fibrosis and/or Renal tubular atrophy.
Raynaud phenomenon
MedGen UID:
20474
Concept ID:
C0034735
Disease or Syndrome
An episodic vasoconstriction resulting in discoloration of the skin and pain in the affected areas, often involving fingers or toes. Classically associated with triphasic color changes (white, blue, red) but may be biphasic. Often occurs in response to cold temperatures or emotional stress. May be primary or secondary to an underlying autoimmune disease.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Spastic diplegia
MedGen UID:
44181
Concept ID:
C0023882
Disease or Syndrome
Spasticity (neuromuscular hypertonia) primarily in the muscles of the legs, hips, and pelvis.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Progressive spastic quadriplegia
MedGen UID:
347944
Concept ID:
C1859736
Finding
Rheumatoid arthritis
MedGen UID:
2078
Concept ID:
C0003873
Disease or Syndrome
Rheumatoid arthritis is an inflammatory disease, primarily of the joints, with autoimmune features and a complex genetic component.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Joint swelling
MedGen UID:
56258
Concept ID:
C0152031
Finding
The presence of swelling in a joint.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Barrel-shaped chest
MedGen UID:
120497
Concept ID:
C0264172
Finding
A rounded, bulging chest that resembles the shape of a barrel. That is, there is an increased anteroposterior diameter and usually some degree of kyphosis.
Cerebral calcification
MedGen UID:
124360
Concept ID:
C0270685
Finding
The presence of calcium deposition within the cerebrum.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Lumbar hyperlordosis
MedGen UID:
263149
Concept ID:
C1184923
Finding
An abnormal accentuation of the inward curvature of the spine in the lumbar region.
Metaphyseal irregularity
MedGen UID:
325478
Concept ID:
C1838662
Finding
Irregularity of the normally smooth surface of the metaphyses.
Irregular vertebral endplates
MedGen UID:
331233
Concept ID:
C1842153
Finding
An irregular surface of the vertebral end plates, which are normally relatively smooth.
Platyspondyly
MedGen UID:
335010
Concept ID:
C1844704
Finding
A flattened vertebral body shape with reduced distance between the vertebral endplates.
Metaphyseal widening
MedGen UID:
341364
Concept ID:
C1849039
Finding
Abnormal widening of the metaphyseal regions of long bones.
Short iliac bones
MedGen UID:
336488
Concept ID:
C1849063
Finding
Underdevelopment of the iliac bones.
Sclerosis of skull base
MedGen UID:
377095
Concept ID:
C1851714
Finding
Increased bone density of the skull base without significant changes in bony contour.
Metaphyseal sclerosis
MedGen UID:
765440
Concept ID:
C3552526
Finding
Abnormally increased density of metaphyseal bone.
Juvenile rheumatoid arthritis
MedGen UID:
811462
Concept ID:
C3714757
Disease or Syndrome
An older, deprecated term that encompassed three major types of autoimmune or autoinflammatory arthritis in children: systemic-onset, pauciarticular, or polyarticular arthritis. The juvenile rheumatoid arthritis classification system has been replaced by the International League of Associations for Rheumatology (ILAR) juvenile idiopathic arthritis classification system.
Increased intervertebral space
MedGen UID:
868122
Concept ID:
C4022513
Finding
An increase in the vertical distance between adjacent vertebral bodies, observed as an increase in the intervertebral disk space.
Spondylometaphyseal dysplasia
MedGen UID:
1674850
Concept ID:
C4759767
Disease or Syndrome
A heterogeneous group of disorders associated with walking and growth disturbances that become evident during the second year of life. Characteristics are platyspondyly (flattened vertebrae) and marked hip and knee metaphyseal lesions. The different forms of spondylometaphyseal dysplasia are distinguished by the localisation and severity of involvement of the affected metaphyses.
Metaphyseal dysplasia
MedGen UID:
1677924
Concept ID:
C5194606
Disease or Syndrome
The presence of dysplastic regions in metaphyseal regions.
Turricephaly
MedGen UID:
1726910
Concept ID:
C5399823
Congenital Abnormality
Tall head relative to width and length.
Recurrent sinusitis
MedGen UID:
107919
Concept ID:
C0581354
Disease or Syndrome
A recurrent form of sinusitis.
Restrictive ventilatory defect
MedGen UID:
478856
Concept ID:
C3277226
Finding
A functional defect characterized by reduced total lung capacity (TLC) not associated with abnormalities of expiratory airflow or airway resistance. Spirometrically, a restrictive defect is defined as FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) less than 80 per cent. Restrictive lung disease may be caused by alterations in lung parenchyma or because of a disease of the pleura, chest wall, or neuromuscular apparatus.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Autoimmunity
MedGen UID:
2136
Concept ID:
C0004368
Pathologic Function
The occurrence of an immune reaction against the organism's own cells or tissues.
Systemic lupus erythematosus
MedGen UID:
6146
Concept ID:
C0024141
Disease or Syndrome
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by production of autoantibodies against nuclear, cytoplasmic, and cell surface molecules that transcend organ-specific boundaries. Tissue deposition of antibodies or immune complexes induces inflammation and subsequent injury of multiple organs and finally results in clinical manifestations of SLE, including glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, and arthritis. Evidence strongly suggests the involvement of genetic components in SLE susceptibility (summary by Oishi et al., 2008). Genetic Heterogeneity of Systemic Lupus Erythematosus An autosomal recessive form of systemic lupus erythematosus (SLEB16; 614420) is caused by mutation in the DNASE1L3 gene (602244) on chromosome 3p14.3. An X-linked dominant form of SLE (SLEB17; 301080) is caused by heterozygous mutation in the TLR7 gene (300365) on chromosome Xp22. See MAPPING and MOLECULAR GENETICS sections for a discussion of genetic heterogeneity of susceptibility to SLE.
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Pneumonia
MedGen UID:
10813
Concept ID:
C0032285
Disease or Syndrome
Inflammation of any part of the lung parenchyma.
Antinuclear antibody positivity
MedGen UID:
101792
Concept ID:
C0151480
Laboratory or Test Result
The presence of autoantibodies in the serum that react against nuclei or nuclear components.
Autoimmune thrombocytopenia
MedGen UID:
116621
Concept ID:
C0242584
Disease or Syndrome
The presence of thrombocytopenia in combination with detection of antiplatelet antibodies.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargement (swelling) of a lymph node.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Immune dysregulation
MedGen UID:
335001
Concept ID:
C1844666
Finding
Altered immune function characterized by lymphoid proliferation, immune activation, and excessive autoreactivity often leading to autoimmune/inflammatory complications.
Cellular immunodeficiency
MedGen UID:
344444
Concept ID:
C1855204
Finding
An immunodeficiency characterized by defective cell-mediated immunity or humoral immunity.
Combined immunodeficiency
MedGen UID:
751396
Concept ID:
C2711630
Disease or Syndrome
A group of phenotypically heterogeneous genetic disorders characterized by profound deficiencies of T- and B-cell function, which predispose the patients to both infectious and noninfectious complications.
T lymphocytopenia
MedGen UID:
419385
Concept ID:
C2931322
Finding
An abnormally low count of T cells.
Narrow nose
MedGen UID:
98086
Concept ID:
C0426422
Finding
Interalar distance more than 2 SD below the mean for age, or alternatively, an apparently decreased width of the nasal base and alae.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Purpura
MedGen UID:
19584
Concept ID:
C0034150
Disease or Syndrome
Purpura (from Latin
Vitiligo
MedGen UID:
22677
Concept ID:
C0042900
Disease or Syndrome
Generalized well circumscribed patches of leukoderma that are generally distributed over symmetric body locations and is due to autoimmune destruction of melanocytes.
Hypermelanotic macule
MedGen UID:
375013
Concept ID:
C1842774
Finding
A hyperpigmented circumscribed area of change in normal skin color without elevation or depression of any size.
Hypopigmented skin patches on arms
MedGen UID:
870407
Concept ID:
C4024852
Finding
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.

Professional guidelines

PubMed

Li W, Wang W, Wang W, Zhong L, Gou L, Wang C, Ma J, Quan M, Jian S, Tang X, Zhang Y, Wang L, Ma M, Song H
Front Immunol 2022;13:825367. Epub 2022 Mar 28 doi: 10.3389/fimmu.2022.825367. PMID: 35418997Free PMC Article

Recent clinical studies

Etiology

Nelson CP, Schunkert H, Samani NJ, Erridge C
Arterioscler Thromb Vasc Biol 2015 Jun;35(6):1456-62. Epub 2015 Apr 16 doi: 10.1161/ATVBAHA.114.304925. PMID: 25882064

Diagnosis

Dri J, Dos Santos E, Pereyra M, Guillamondegui MJ, Ballester C, Tolin A, Gatica C
Arch Argent Pediatr 2024 Feb 1;122(1):e202303031. Epub 2023 Jul 6 doi: 10.5546/aap.2023-03031.eng. PMID: 37382551
Sait H, Gangadharan H, Gupta A, Aggarwal A, Jain M, Phadke SR
Indian J Pediatr 2021 Aug;88(8):819-823. Epub 2021 Mar 13 doi: 10.1007/s12098-020-03636-x. PMID: 33712926

Therapy

Li W, Wang W, Wang W, Zhong L, Gou L, Wang C, Ma J, Quan M, Jian S, Tang X, Zhang Y, Wang L, Ma M, Song H
Front Immunol 2022;13:825367. Epub 2022 Mar 28 doi: 10.3389/fimmu.2022.825367. PMID: 35418997Free PMC Article
Nelson CP, Schunkert H, Samani NJ, Erridge C
Arterioscler Thromb Vasc Biol 2015 Jun;35(6):1456-62. Epub 2015 Apr 16 doi: 10.1161/ATVBAHA.114.304925. PMID: 25882064

Prognosis

Dri J, Dos Santos E, Pereyra M, Guillamondegui MJ, Ballester C, Tolin A, Gatica C
Arch Argent Pediatr 2024 Feb 1;122(1):e202303031. Epub 2023 Jul 6 doi: 10.5546/aap.2023-03031.eng. PMID: 37382551

Clinical prediction guides

Dri J, Dos Santos E, Pereyra M, Guillamondegui MJ, Ballester C, Tolin A, Gatica C
Arch Argent Pediatr 2024 Feb 1;122(1):e202303031. Epub 2023 Jul 6 doi: 10.5546/aap.2023-03031.eng. PMID: 37382551
Li W, Wang W, Wang W, Zhong L, Gou L, Wang C, Ma J, Quan M, Jian S, Tang X, Zhang Y, Wang L, Ma M, Song H
Front Immunol 2022;13:825367. Epub 2022 Mar 28 doi: 10.3389/fimmu.2022.825367. PMID: 35418997Free PMC Article
Sait H, Gangadharan H, Gupta A, Aggarwal A, Jain M, Phadke SR
Indian J Pediatr 2021 Aug;88(8):819-823. Epub 2021 Mar 13 doi: 10.1007/s12098-020-03636-x. PMID: 33712926
Briggs TA, Rice GI, Adib N, Ades L, Barete S, Baskar K, Baudouin V, Cebeci AN, Clapuyt P, Coman D, De Somer L, Finezilber Y, Frydman M, Guven A, Heritier S, Karall D, Kulkarni ML, Lebon P, Levitt D, Le Merrer M, Linglart A, Livingston JH, Navarro V, Okenfuss E, Puel A, Revencu N, Scholl-Bürgi S, Vivarelli M, Wouters C, Bader-Meunier B, Crow YJ
J Clin Immunol 2016 Apr;36(3):220-34. Epub 2016 Mar 8 doi: 10.1007/s10875-016-0252-y. PMID: 26951490Free PMC Article
Nelson CP, Schunkert H, Samani NJ, Erridge C
Arterioscler Thromb Vasc Biol 2015 Jun;35(6):1456-62. Epub 2015 Apr 16 doi: 10.1161/ATVBAHA.114.304925. PMID: 25882064

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