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Dubowitz syndrome

General Information (adopted from Orphanet):

Synonyms, Signs:
Number of Symptoms	138
OrphanetNr:	235
OMIM Id:	223370
ICD-10:	Q87.1
UMLs:	C0175691
MeSH:	C535718
MedDRA:	10059589
Snomed:	2593002

Prevalence, inheritance and age of onset:

Prevalence:	0.2 of 100 000 [Orphanet]
Inheritance:	Autosomal recessive [Orphanet]
Age of onset:	Antenatal Neonatal [Orphanet]

Disease classification (adopted from Orphanet):

Parent Diseases:

Ectodermal dysplasia syndrome
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare skin disease
Genetic malformation syndrome with short stature
-Rare genetic disease
Malformation syndrome with short stature
-Rare developmental defect during embryogenesis
Multiple congenital anomalies/dysmorphic syndrome-intellectual deficit
-Rare developmental defect during embryogenesis
-Rare genetic disease
Ptosis
-Rare eye disease
-Rare genetic disease
Rare genetic intellectual deficit with developmental anomaly
-Rare genetic disease
Rare intellectual deficit with developmental anomaly
-Rare neurologic disease

Symptom Information: Sort by abundance

	Symptom Information	Symptom	Abundance	DB Freq
1	(HPO:0002028)	Chronic diarrhea		51 / 7739
2	(HPO:0011968)	Feeding difficulties		240 / 7739
3	(HPO:0008872)	Feeding difficulties in infancy		153 / 7739
4	(HPO:0002572)	Episodic vomiting		12 / 7739
5	(HPO:0000960)	Sacral dimple		29 / 7739
6	(HPO:0010769)	Pilonidal sinus	Occasional [Orphanet]	35 / 7739
7	(HPO:0000316)	Hypertelorism	Very frequent [Orphanet]	644 / 7739
8	(HPO:0000568)	Microphthalmia		183 / 7739
9	(HPO:0000485)	Megalocornea		26 / 7739
10	(HPO:0007676)	Hypoplasia of the iris		22 / 7739
11	(HPO:0000612)	Iris coloboma		116 / 7739
12	(HPO:0000518)	Cataract	Occasional [Orphanet]	454 / 7739
13	(HPO:0000547)	Tapetoretinal degeneration		11 / 7739
14	(HPO:0000639)	Nystagmus	Occasional [Orphanet]	555 / 7739
15	(HPO:0000486)	Strabismus	Occasional [Orphanet]	576 / 7739
16	(HPO:0000540)	Hypermetropia		99 / 7739
17	(HPO:0000545)	Myopia	Occasional [Orphanet]	286 / 7739
18	(HPO:0000508)	Ptosis	Frequent [Orphanet]	459 / 7739
19	(HPO:0002099)	Asthma	Occasional [Orphanet]	62 / 7739
20	(HPO:0002093)	Respiratory insufficiency	Frequent [Orphanet]	410 / 7739
21	(HPO:0001620)	High pitched voice		32 / 7739
22	(HPO:0004322)	Short stature	Very frequent [Orphanet]	1232 / 7739
23	(HPO:0004325)	Decreased body weight	Frequent [Orphanet]	492 / 7739
24	(HPO:0001915)	Aplastic anemia		16 / 7739
25	(HPO:0030680)	Abnormality of cardiovascular system morphology	Occasional [Orphanet]	355 / 7739
26	(HPO:0001903)	Anemia	Occasional [Orphanet]	289 / 7739
27	(HPO:0010978)	Abnormality of immune system physiology	Frequent [Orphanet]	148 / 7739
28	(HPO:0004313)	Decreased antibody level in blood		47 / 7739
29	(HPO:0002720)	IgA deficiency		33 / 7739
30	(HPO:0004315)	IgG deficiency		38 / 7739
31	(HPO:0002719)	Recurrent infections		107 / 7739
32	(HPO:0001874)	Abnormality of neutrophils	Occasional [Orphanet]	47 / 7739
33	(HPO:0006721)	Acute lymphoblastic leukemia		7 / 7739
34	(HPO:0001252)	Muscular hypotonia		990 / 7739
35	(HPO:0008947)	Infantile muscular hypotonia		482 / 7739
36	(HPO:0010547)	Muscle flaccidity		466 / 7739
37	(HPO:0001324)	Muscle weakness		859 / 7739
38	(HPO:0003006)	Neuroblastoma		16 / 7739
39	(HPO:0001249)	Intellectual disability	10% [HPO:probinson]	1089 / 7739
40	(HPO:0000736)	Short attention span		16 / 7739
41	(HPO:0000750)	Delayed speech and language development		197 / 7739
42	(HPO:0000752)	Hyperactivity	Frequent [Orphanet]	140 / 7739
43	(HPO:0001250)	Seizures	Occasional [Orphanet]	1245 / 7739
44	(HPO:0001511)	Intrauterine growth retardation	Very frequent [Orphanet]	358 / 7739
45	(HPO:0004209)	Clinodactyly of the 5th finger	Frequent [Orphanet]	288 / 7739
46	(HPO:0001172)	Abnormality of the thumb	Very frequent [Orphanet]	103 / 7739
47	(HPO:0009601)	Aplasia/Hypoplasia of the thumb	Very frequent [Orphanet]	80 / 7739
48	(HPO:0001840)	Metatarsus adductus	Occasional [Orphanet]	49 / 7739
49	(HPO:0001852)	Sandal gap	Frequent [Orphanet]	63 / 7739
50	(HPO:0001770)	Toe syndactyly	Occasional [Orphanet]	149 / 7739
51	(HPO:0001762)	Talipes equinovarus	Occasional [Orphanet]	309 / 7739
52	(HPO:0001763)	Pes planus		176 / 7739
53	(HPO:0001773)	Short foot	Frequent [Orphanet]	86 / 7739
54	(HPO:0004279)	Short palm	Occasional [Orphanet]	323 / 7739
55	(HPO:0200055)	Small hand	Frequent [Orphanet]	71 / 7739
56	(HPO:0000277)	Abnormality of the mandible	Frequent [Orphanet]	394 / 7739
57	(HPO:0000347)	Micrognathia		426 / 7739
58	(HPO:0001363)	Craniosynostosis	Occasional [Orphanet]	132 / 7739
59	(HPO:0000348)	High forehead		157 / 7739
60	(HPO:0000239)	Large fontanelles	Frequent [Orphanet]	135 / 7739
61	(HPO:0000294)	Low anterior hairline	Frequent [Orphanet]	52 / 7739
62	(HPO:0000252)	Microcephaly	Very frequent [Orphanet]	832 / 7739
63	(HPO:0000340)	Sloping forehead	Frequent [Orphanet]	86 / 7739
64	(HPO:0000767)	Pectus excavatum	Occasional [Orphanet]	244 / 7739
65	(HPO:0002650)	Scoliosis	Occasional [Orphanet]	705 / 7739
66	(HPO:0003298)	Spina bifida occulta	Occasional [Orphanet]	67 / 7739
67	(HPO:0007370)	Aplasia/Hypoplasia of the corpus callosum	Occasional [Orphanet]	180 / 7739
68	(HPO:0001382)	Joint hypermobility	Occasional [Orphanet]	231 / 7739
69	(HPO:0002750)	Delayed skeletal maturation	Frequent [Orphanet]	250 / 7739
70	(HPO:0002213)	Fine hair	Frequent [Orphanet]	77 / 7739
71	(HPO:0005338)	Sparse lateral eyebrow	Frequent [Orphanet]	21 / 7739
72	(HPO:0001006)	Hypotrichosis	Frequent [Orphanet]	219 / 7739
73	(HPO:0002209)	Sparse scalp hair		59 / 7739
74	(HPO:0001231)	Abnormality of the fingernails	Occasional [Orphanet]	116 / 7739
75	(HPO:0001800)	Hypoplastic toenails	Occasional [Orphanet]	74 / 7739
76	(HPO:0004378)	Abnormality of the anus	Occasional [Orphanet]	34 / 7739
77	(HPO:0002020)	Gastroesophageal reflux		101 / 7739
78	(HPO:0002024)	Malabsorption	Occasional [Orphanet]	142 / 7739
79	(HPO:0000023)	Inguinal hernia		181 / 7739
80	(HPO:0000047)	Hypospadias	Frequent [Orphanet]	250 / 7739
81	(HPO:0000028)	Cryptorchidism		347 / 7739
82	(HPO:0000035)	Abnormality of the testis	Frequent [Orphanet]	296 / 7739
83	(HPO:0000324)	Facial asymmetry		57 / 7739
84	(HPO:0000275)	Narrow face	Frequent [Orphanet]	76 / 7739
85	(HPO:0000274)	Small face		18 / 7739
86	(HPO:0009891)	Underdeveloped supraorbital ridges	Very frequent [Orphanet]	36 / 7739
87	(HPO:0000174)	Abnormality of the palate	Occasional [Orphanet]	298 / 7739
88	(HPO:0000220)	Velopharyngeal insufficiency		10 / 7739
89	(HPO:0000185)	Cleft soft palate		18 / 7739
90	(HPO:0000218)	High palate		356 / 7739
91	(HPO:0002705)	High, narrow palate	Occasional [Orphanet]	308 / 7739
92	(HPO:0000176)	Submucous cleft hard palate		19 / 7739
93	(HPO:0011819)	Submucous cleft soft palate		12 / 7739
94	(HPO:0000164)	Abnormality of the teeth	Occasional [Orphanet]	291 / 7739
95	(HPO:0006349)	Agenesis of permanent teeth		13 / 7739
96	(HPO:0000670)	Carious teeth		145 / 7739
97	(HPO:0000684)	Delayed eruption of teeth	Occasional [Orphanet]	117 / 7739
98	(HPO:0000154)	Wide mouth	Occasional [Orphanet]	137 / 7739
99	(HPO:0000455)	Broad nasal tip		67 / 7739
100	(HPO:0005280)	Depressed nasal bridge	Frequent [Orphanet]	381 / 7739
101	(HPO:0000431)	Wide nasal bridge		290 / 7739
102	(HPO:0000581)	Blepharophimosis	Frequent [Orphanet]	197 / 7739
103	(HPO:0000286)	Epicanthus	Frequent [Orphanet]	371 / 7739
104	(HPO:0000506)	Telecanthus	Very frequent [Orphanet]	156 / 7739
105	(HPO:0000388)	Otitis media		28 / 7739
106	(HPO:0000357)	Abnormal location of ears	Frequent [Orphanet]	328 / 7739
107	(HPO:0009738)	Abnormality of the antihelix	Frequent [Orphanet]	37 / 7739
108	(HPO:0000377)	Abnormality of the pinna		111 / 7739
109	(HPO:0000369)	Low-set ears		372 / 7739
110	(HPO:0000411)	Protruding ear	Frequent [Orphanet]	140 / 7739
111	(HPO:0000829)	Hypoparathyroidism	Occasional [Orphanet]	22 / 7739
112	(HPO:0001000)	Abnormality of skin pigmentation	Occasional [Orphanet]	105 / 7739
113	(HPO:0000992)	Cutaneous photosensitivity	Occasional [Orphanet]	75 / 7739
114	(HPO:0000965)	Cutis marmorata	Occasional [Orphanet]	46 / 7739
115	(HPO:0000958)	Dry skin	Occasional [Orphanet]	152 / 7739
116	(HPO:0001047)	Atopic dermatitis		20 / 7739
117	(HPO:0000964)	Eczema	Frequent [Orphanet]	81 / 7739
118	(HPO:0000976)	Eczematoid dermatitis		22 / 7739
119	(HPO:0001051)	Seborrheic dermatitis		25 / 7739
120	(HPO:0000072)	Hydroureter	Occasional [Orphanet]	146 / 7739
121	(HPO:0001873)	Thrombocytopenia	Occasional [Orphanet]	224 / 7739
122	(HPO:0008897)	Postnatal growth retardation		113 / 7739
123	(HPO:0000365)	Hearing impairment	Frequent [Orphanet]	539 / 7739
124	(HPO:0004377)	Hematological neoplasm	Occasional [Orphanet]	12 / 7739
125	(HPO:0002665)	Lymphoma	Occasional [Orphanet]	60 / 7739
126	(HPO:0002664)	Neoplasm	Occasional [Orphanet]	111 / 7739
127	(HPO:0000007)	Autosomal recessive inheritance		2538 / 7739
128	(HPO:0000238)	Hydrocephalus	Occasional [Orphanet]	278 / 7739
129	(HPO:0012815)	Hypoplastic female external genitalia	Frequent [Orphanet]	36 / 7739
130	(HPO:0012758)	Neurodevelopmental delay	Very frequent [Orphanet]	949 / 7739
131	(HPO:0012745)	Short palpebral fissure		47 / 7739
132	(OMIM)	Average birth head circumference 30.6cm		1 / 7739
133	(OMIM)	Average birth length 44cm		1 / 7739
134	(OMIM)	Average birth weight 2.3kg		1 / 7739
135	(OMIM)	Elongation of face with age		1 / 7739
136	(OMIM)	High, sloping forehead		2 / 7739
137	(OMIM)	Mental retardation, moderate to severe		20 / 7739
138	(OMIM)	Two-three toe syndactyly		1 / 7739

Associated genes:

ClinVar (via SNiPA)

Gene symbol	Variation	Clinical significance	Reference

Additional Information:

Clinical Description OMIM

Dubowitz (1965) reported 4 patients with a malformation syndrome characterized by intrauterine growth retardation, short stature, microcephaly, mild mental retardation with behavior problems, eczema, and unusual and distinctive facies. Various minor malformations, such as pilonidal dimples, submucous clefts, ... Dubowitz (1965) reported 4 patients with a malformation syndrome characterized by intrauterine growth retardation, short stature, microcephaly, mild mental retardation with behavior problems, eczema, and unusual and distinctive facies. Various minor malformations, such as pilonidal dimples, submucous clefts, high-pitched voice and sparse hair, were also seen. Two of the 4 cases were full sibs with nonconsanguineous parents. An older sib of Dubowitz's original proband was probably affected but studies were not done at her death. Grosse et al. (1971) added 2 more cases. Features were intrauterine growth retardation (with primordial shortness of stature), microcephaly, variable degrees of eczema and mental retardation, and characteristic facies (blepharophimosis, micrognathia, apparent hypertelorism). Opitz et al. (1973) concluded that eczema may be absent, stature may be normal, and intelligence may also be normal, although head circumference is always below the third percentile. They observed first-cousin parents. Wilroy et al. (1978) reviewed 13 reported cases and 8 personally examined patients, including affected monozygotic twins and sibs. They pointed to the occurrence of hypospadias, cryptorchidism and ptosis. Orrison et al. (1980) reported 5 cases of which 2 had documented abnormalities: complete occlusion of the internal carotid artery and aberrant right subclavian artery. Parrish and Wilroy (1980) characterized the voice as hoarse as well as high-pitched. They found that intelligence varied from severe retardation to average levels. Moller and Gorlin (1985) gave a follow-up of the cases reported by Grosse et al. (1971) and stated that high-pitched, hoarse voice seems to be a constant feature. See also review of Winter (1986). Kuster and Majewski (1986) reported 5 sporadic cases and found 33 cases in the literature. The case reported by Kondo et al. (1987) demonstrates that the syndrome occurs in Orientals as well as in Caucasians. On the basis of 21 personal observations and a review of the literature, Ilyina and Lurie (1990) pointed out that, in spite of marked microcephaly, severe mental deficiency is rare in Dubowitz syndrome and about half the patients are mentally normal. They suggested the existence of a 'new' clinical subtype that includes anorectal anomalies and premature craniosynostosis. All 3 families with this subtype were natives of a restricted area of Byelorussia called Polessie (Woodland). Lerman-Sagie et al. (1990) described 2 new manifestations: velopharyngeal insufficiency and hypoparathyroidism. The affected child had fully recovered from 'transient' congenital hypoparathyroidism but redeveloped the disorder at age 6 years. Thuret et al. (1991) reported the cases of 2 Caucasian sisters who, in addition to other features, had repeated infections and recurrent ulcerative stomatitis. They suffered from recurrent neutropenia. One had complete IgA deficiency with elevated IgM levels; the other had low values of both IgA and IgG with an increased level of IgM. An increased rate of chromosomal breakage was demonstrated in both. Thus, the disorder shares features with Fanconi anemia (227650). The frequency of malignant tumors may be increased in the Dubowitz syndrome. Bone marrow failure had previously been reported in 5 patients (Walters and Desposito, 1985; Berthold et al., 1987; Ilyina and Lurie, 1990). The lack of a basic biochemical characterization of Dubowitz syndrome makes it impossible to be completely certain of the diagnosis in these cases. Lyonnet et al. (1992) commented on the paucity of information on the clinical features of Dubowitz syndrome in older patients. This deficiency was corrected in part by Hansen et al. (1995) who described long-term follow-up of one of the first patients to be diagnosed with Dubowitz syndrome (Grosse et al., 1971). Photographs of her in infancy and childhood were used to illustrate the publication by Grosse et al. (1971) and were reprinted in 'Smith's Recognizable Patterns of Human Malformation' (Jones, 1988). Hansen et al. (1995) provided pictures at the age of 30 years. Microcephaly, short stature, leg length discrepancy, hyperextensible joints, spina bifida occulta, and absence of anterior cruciate ligaments were present. Her facial appearance had been modified by several plastic surgery procedures. Eczema resolved with age, with occasional flareups. Asthma, headaches, and seizures were additional medical problems. Speech delays, an unusually soft and high-pitched voice, submucous cleft palate, and velopharyngeal insufficiency were noted in childhood. Mild mental retardation was present. At the age of 30 years, the patient lived independently and worked full time in a sheltered workshop. Tsukahara and Opitz (1996) reviewed clinical information on 141 individuals with Dubowitz syndrome, 105 reported since 1965, and 36 previously unreported. They suggested that facial anomalies are perhaps the most diagnostic of the physical signs. Microcephaly was present in 112 of the patients, blepharophimosis in 60, and ptosis in 53. They considered a prominent round tip of the nose, noted in 17 of their 34 cases, to be especially characteristic of the Dubowitz syndrome at a young age. In the total of 141 patients, normal appearance was found 15 times. Affected sibs were found in 9 families, with both sexes being affected. In 2 of 15 familial cases, the parents were consanguineous. One set of concordantly affected monozygotic twins was known, as well as a set of dizygotic twins with only 1 twin affected. Ahmad et al. (1999) reported a girl with Dubowitz syndrome and a persistently low cholesterol level. Plasma cholesterol levels persistently ranged from 60 to 80 mg/dl (normal is more than 100 mg/dl). Other components of the cholesterol profile (e.g., low density lipoprotein and high density lipoprotein) were normal, as were the cholesterol levels in both parents. A 7-dehydrocholesterol level was normal, ruling out Smith-Lemli-Opitz syndrome (270400). Plasma sterol analysis by GC/MS was also normal. The authors suggested that Dubowitz syndrome may represent another disorder caused by an alteration in sterol synthesis or transport, or metabolism. Al-Nemri et al. (2000) reported a newborn girl with possible Dubowitz syndrome, who also had embryonal rhabdomyosarcoma and multiple spontaneous chromosome breaks. The tumor was resected, but recurred, resulting in the infant's death at age 3 months. Yesilkaya et al. (2008) reported a 16-year-old boy, born of consanguineous Turkish parents, with short stature, delayed psychomotor development, and dysmorphic facial features most consistent with a diagnosis of Dubowitz syndrome. Brain MRI showed an arachnoid cyst and laboratory studies showed persistently low serum lipid levels. Yesilkaya et al. (2008) noted that Ahmad et al. (1999) had also reported an association between Dubowitz syndrome and low cholesterol.

Symptoms & Signs

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