Wolf-Hirschhorn syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: PITT SYNDROME
PITT-ROGERS-DANKS SYNDROME
WHS
PRDS
CHROMOSOME 4p16.3 DELETION SYNDROME
Telomeric deletion 4p
Distal deletion 4p
Distal monosomy 4p
4p- syndrome
Number of Symptoms 165
OrphanetNr: 280
OMIM Id: 194190
ICD-10: Q93.3
UMLs: C1956097
MeSH: C536740
D054877
MedDRA: 10050361
Snomed: 17122004

Prevalence, inheritance and age of onset:

Prevalence: 2 of 100 000 [Orphanet]
Inheritance: Unknown
Not applicable
[Orphanet]
Age of onset: Antenatal
Neonatal
[Orphanet]

Disease classification (adopted from Orphanet):

Parent Diseases: Chromosomal anomaly with cataract
 -Rare eye disease
 -Rare genetic disease
Chromosomal anomaly with epilepsy as a major feature
 -Rare neurologic disease
Partial deletion of the short arm of chromosome 4
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
Syndromic diaphragmatic or abdominal wall malformation
 -Rare abdominal surgical disease
 -Rare developmental defect during embryogenesis
Syndromic diaphragmatic or thoracic malformation
 -Rare surgical thoracic disease
Syndromic genetic deafness
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare otorhinolaryngologic disease

Symptom Information: Sort by abundance 

1
(HPO:0000078) Abnormality of the genital system Occasional [Orphanet] 33 / 7739
2
(HPO:0000079) Abnormality of the urinary system Occasional [Orphanet] 88 / 7739
3
(HPO:0000047) Hypospadias Very frequent [Orphanet] 50% [HPO] 250 / 7739
4
(HPO:0000151) Aplasia of the uterus rare [HPO] 12 / 7739
5
(HPO:0000035) Abnormality of the testis Frequent [Orphanet] 296 / 7739
6
(HPO:0000077) Abnormality of the kidney Frequent [Orphanet] 73 / 7739
7
(HPO:0000028) Cryptorchidism 50% [HPO] 347 / 7739
8
(HPO:0000268) Dolichocephaly Very frequent [Orphanet] 144 / 7739
9
(HPO:0000267) Cranial asymmetry 6 / 7739
10
(HPO:0000322) Short philtrum Very frequent [Orphanet] typical [HPO] 130 / 7739
11
(HPO:0000316) Hypertelorism Very frequent [Orphanet] typical [HPO] 644 / 7739
12
(HPO:0000465) Webbed neck rare [HPO] 81 / 7739
13
(HPO:0002162) Low posterior hairline 88 / 7739
14
(HPO:0000348) High forehead Very frequent [Orphanet] typical [HPO] 157 / 7739
15
(HPO:0000174) Abnormality of the palate Occasional [Orphanet] 298 / 7739
16
(HPO:0000252) Microcephaly Very frequent [Orphanet] typical [HPO] 832 / 7739
17
(HPO:0000153) Abnormality of the mouth Very frequent [Orphanet] 60 / 7739
18
(HPO:0009804) Reduced number of teeth Very frequent [Orphanet] 137 / 7739
19
(HPO:0000202) Oral cleft Frequent [Orphanet] 120 / 7739
20
(HPO:0002057) Prominent glabella typical [HPO] 8 / 7739
21
(HPO:0000188) Short upper lip typical [HPO] 8 / 7739
22
(HPO:0002714) Downturned corners of mouth Very frequent [Orphanet] typical [HPO] 98 / 7739
23
(HPO:0000277) Abnormality of the mandible Very frequent [Orphanet] 394 / 7739
24
(HPO:0000431) Wide nasal bridge typical [HPO] 290 / 7739
25
(HPO:0000286) Epicanthus Very frequent [Orphanet] typical [HPO] 371 / 7739
26
(HPO:0000494) Downslanted palpebral fissures Very frequent [Orphanet] 328 / 7739
27
(HPO:0001362) Calvarial skull defect Frequent [Orphanet] 22 / 7739
28
(HPO:0000204) Cleft upper lip 193 / 7739
29
(HPO:0000347) Micrognathia typical [HPO] 426 / 7739
30
(HPO:0002553) Highly arched eyebrow Very frequent [Orphanet] typical [HPO] 92 / 7739
31
(HPO:0000175) Cleft palate 349 / 7739
32
(HPO:0000445) Wide nose Very frequent [Orphanet] 190 / 7739
33
(HPO:0004484) Craniofacial asymmetry typical [HPO] 3 / 7739
34
(HPO:0000668) Hypodontia typical [HPO] 81 / 7739
35
(HPO:0000349) Widow's peak Very frequent [Orphanet] 26 / 7739
36
(HPO:0002007) Frontal bossing Very frequent [Orphanet] 366 / 7739
37
(HPO:0000520) Proptosis Occasional [Orphanet] frequent [HPO] 192 / 7739
38
(HPO:0000444) Convex nasal ridge typical [HPO] 87 / 7739
39
(HPO:0000485) Megalocornea Occasional [Orphanet] 26 / 7739
40
(HPO:0000639) Nystagmus Occasional [Orphanet] typical [HPO] 555 / 7739
41
(HPO:0000486) Strabismus Occasional [Orphanet] typical [HPO] 576 / 7739
42
(HPO:0000612) Iris coloboma Frequent [Orphanet] 30% [HPO] 116 / 7739
43
(HPO:0009918) Ectopia pupillae 6 / 7739
44
(HPO:0000488) Retinopathy Occasional [Orphanet] 75 / 7739
45
(HPO:0000558) Rieger anomaly typical [HPO] 5 / 7739
46
(HPO:0000508) Ptosis Frequent [Orphanet] common [HPO] 459 / 7739
47
(HPO:0000647) Sclerocornea Occasional [Orphanet] 25 / 7739
48
(HPO:0000407) Sensorineural hearing impairment 15% [HPO] 524 / 7739
49
(HPO:0000384) Preauricular skin tag typical [HPO] 62 / 7739
50
(HPO:0000377) Abnormality of the pinna typical [HPO] 111 / 7739
51
(HPO:0000389) Chronic otitis media Occasional [Orphanet] 64 / 7739
52
(HPO:0000402) Stenosis of the external auditory canal typical [HPO] 22 / 7739
53
(HPO:0000405) Conductive hearing impairment 40% [HPO] 164 / 7739
54
(HPO:0000365) Hearing impairment Frequent [Orphanet] 539 / 7739
55
(HPO:0004467) Preauricular pit typical [HPO] 39 / 7739
56
(HPO:0000357) Abnormal location of ears Very frequent [Orphanet] 328 / 7739
57
(HPO:0008772) Aplasia/Hypoplasia of the external ear Very frequent [Orphanet] 67 / 7739
58
(HPO:0001263) Global developmental delay hallmark [HPO] 853 / 7739
59
(HPO:0001250) Seizures Very frequent [Orphanet] common [HPO] 1245 / 7739
60
(HPO:0000733) Stereotypy frequent [HPO] 58 / 7739
61
(HPO:0002066) Gait ataxia Very frequent [Orphanet] 327 / 7739
62
(HPO:0010864) Intellectual disability, severe 120 / 7739
63
(HPO:0100022) Abnormality of movement Occasional [Orphanet] 129 / 7739
64
(HPO:0002353) EEG abnormality 90% [HPO] 188 / 7739
65
(HPO:0006709) Aplasia/Hypoplasia of the nipples Occasional [Orphanet] 28 / 7739
66
(HPO:0000826) Precocious puberty 42 / 7739
67
(HPO:0000954) Single transverse palmar crease rare [HPO] 162 / 7739
68
(HPO:0009601) Aplasia/Hypoplasia of the thumb Frequent [Orphanet] 80 / 7739
69
(HPO:0009193) Pseudoepiphyses of the metacarpals 4 / 7739
70
(HPO:0002808) Kyphosis Frequent [Orphanet] frequent [HPO] 289 / 7739
71
(HPO:0001760) Abnormality of the foot Frequent [Orphanet] 96 / 7739
72
(HPO:0003468) Abnormality of the vertebrae Frequent [Orphanet] 77 / 7739
73
(HPO:0000921) Missing ribs Frequent [Orphanet] 62 / 7739
74
(HPO:0006655) Rib segmentation abnormalities frequent [HPO] 2 / 7739
75
(HPO:0001385) Hip dysplasia occasional [HPO] 242 / 7739
76
(HPO:0000960) Sacral dimple rare [HPO] 29 / 7739
77
(HPO:0004349) Reduced bone mineral density Occasional [Orphanet] 165 / 7739
78
(HPO:0001762) Talipes equinovarus Frequent [Orphanet] frequent [HPO] 309 / 7739
79
(HPO:0001177) Preaxial hand polydactyly occasional [HPO] 59 / 7739
80
(HPO:0009611) Bifid distal phalanx of the thumb Frequent [Orphanet] 15 / 7739
81
(HPO:0011302) Long palm Frequent [Orphanet] 70 / 7739
82
(HPO:0009778) Short thumb occasional [HPO] 50 / 7739
83
(HPO:0011863) Abnormal sternal ossification 1 / 7739
84
(HPO:0001840) Metatarsus adductus 49 / 7739
85
(HPO:0011867) Abnormality of the wing of the ilium Frequent [Orphanet] 123 / 7739
86
(HPO:0002650) Scoliosis Frequent [Orphanet] frequent [HPO] 705 / 7739
87
(HPO:0001171) Split hand occasional [HPO] 72 / 7739
88
(HPO:0002948) Vertebral fusion 28 / 7739
89
(HPO:0001841) Preaxial foot polydactyly occasional [HPO] 24 / 7739
90
(HPO:0003312) Abnormal form of the vertebral bodies Frequent [Orphanet] frequent [HPO] 20301362 IBIS 172 / 7739
91
(HPO:0002750) Delayed skeletal maturation Frequent [Orphanet] 250 / 7739
92
(HPO:0000902) Rib fusion frequent [HPO] 19 / 7739
93
(HPO:0000765) Abnormality of the thorax Frequent [Orphanet] 64 / 7739
94
(HPO:0010442) Polydactyly 69 / 7739
95
(HPO:0001844) Abnormality of the hallux Frequent [Orphanet] 3 / 7739
96
(HPO:0002827) Hip dislocation 94 / 7739
97
(HPO:0010769) Pilonidal sinus Frequent [Orphanet] 35 / 7739
98
(HPO:0010109) Short hallux occasional [HPO] 27 / 7739
99
(HPO:0002974) Radioulnar synostosis 52 / 7739
100
(HPO:0001155) Abnormality of the hand Frequent [Orphanet] 54 / 7739
101
(HPO:0001558) Decreased fetal movement 74 / 7739
102
(HPO:0001557) Prenatal movement abnormality Very frequent [Orphanet] 16 / 7739
103
(HPO:0001747) Accessory spleen 8 / 7739
104
(HPO:0005264) Abnormality of the gallbladder Occasional [Orphanet] 14 / 7739
105
(HPO:0004794) Malrotation of small bowel 2 / 7739
106
(HPO:0002020) Gastroesophageal reflux 101 / 7739
107
(HPO:0003363) Abdominal situs inversus Occasional [Orphanet] 19 / 7739
108
(HPO:0001080) Biliary tract abnormality rare [HPO] 26 / 7739
109
(HPO:0000775) Abnormality of the diaphragm Frequent [Orphanet] 62 / 7739
110
(HPO:0004299) Hernia of the abdominal wall Occasional [Orphanet] 176 / 7739
111
(HPO:0004322) Short stature common [HPO] 1232 / 7739
112
(HPO:0008850) Severe postnatal growth retardation common [HPO] 16 / 7739
113
(HPO:0004325) Decreased body weight Very frequent [Orphanet] 492 / 7739
114
(HPO:0001508) Failure to thrive common [HPO] 454 / 7739
115
(HPO:0001518) Small for gestational age hallmark [HPO] 107 / 7739
116
(HPO:0001511) Intrauterine growth retardation Very frequent [Orphanet] hallmark [HPO] 358 / 7739
117
(HPO:0001519) Disproportionate tall stature Occasional [Orphanet] 39 / 7739
118
(HPO:0001028) Hemangioma frequent [HPO] 23 / 7739
119
(HPO:0001812) Hyperconvex fingernails 3 / 7739
120
(HPO:0001052) Nevus flammeus Frequent [Orphanet] 88 / 7739
121
(HPO:0007385) Aplasia cutis congenita of scalp occasional [HPO] 10 / 7739
122
(HPO:0004760) Congenital septal defect Frequent [Orphanet] 69 / 7739
123
(HPO:0001629) Ventricular septal defect 316 / 7739
124
(HPO:0001654) Abnormality of the heart valves Frequent [Orphanet] 49 / 7739
125
(HPO:0030680) Abnormality of cardiovascular system morphology Frequent [Orphanet] 355 / 7739
126
(HPO:0001631) Atria septal defect Frequent [Orphanet] 27% [HPO] 274 / 7739
127
(HPO:0003220) Abnormality of chromosome stability Very frequent [Orphanet] 98 / 7739
128
(HPO:0002205) Recurrent respiratory infections Occasional [Orphanet] 254 / 7739
129
(HPO:0006703) Aplasia/Hypoplasia of the lungs Frequent [Orphanet] 79 / 7739
130
(HPO:0002715) Abnormality of the immune system Occasional [Orphanet] 46 / 7739
131
(HPO:0002721) Immunodeficiency 69% [HPO] 97 / 7739
132
(HPO:0001324) Muscle weakness 859 / 7739
133
(HPO:0003199) Decreased muscle mass hallmark [HPO] 27 / 7739
134
(HPO:0008947) Infantile muscular hypotonia 482 / 7739
135
(HPO:0010547) Muscle flaccidity 466 / 7739
136
(HPO:0001252) Muscular hypotonia Very frequent [Orphanet] 990 / 7739
137
(HPO:0001290) Generalized hypotonia hallmark [HPO] 51 / 7739
138
(HPO:0007370) Aplasia/Hypoplasia of the corpus callosum Occasional [Orphanet] 180 / 7739
139
(HPO:0007109) Periventricular cysts 4 / 7739
140
(OMIM) Absence of pubic rami 1 / 7739
141
(HPO:0002389) Cavum septum pellucidum 13 / 7739
142
(HPO:0000006) Autosomal dominant inheritance 2518 / 7739
143
(OMIM) White matter hyperintensities on T2 imaging 1 / 7739
144
(HPO:0001331) Absent septum pellucidum 16 / 7739
145
(OMIM) Bifid vertebrae 1 / 7739
146
(HPO:0002119) Ventriculomegaly 253 / 7739
147
(HPO:0001273) Abnormality of the corpus callosum 20 / 7739
148
(HPO:0000238) Hydrocephalus rare [HPO] 278 / 7739
149
(OMIM) Interventricular cysts 1 / 7739
150
(OMIM) Absence of gallbladder 1 / 7739
151
(HPO:0001274) Agenesis of corpus callosum occasional [HPO] 142 / 7739
152
(OMIM) Sacral sinus 1 / 7739
153
(HPO:0002334) Abnormality of the cerebellar vermis Occasional [Orphanet] 137 / 7739
154
(OMIM) Sparse medial eyebrows 1 / 7739
155
(HPO:0003745) Sporadic 131 / 7739
156
(OMIM) Exophthalmus 1 / 7739
157
(HPO:0012795) Abnormality of the optic disc Frequent [Orphanet] 187 / 7739
158
(HPO:0012758) Neurodevelopmental delay Very frequent [Orphanet] 949 / 7739
159
(OMIM) Marked intrauterine growth retardation 1 / 7739
160
(OMIM) Thin limbs 3 / 7739
161
(HPO:0002144) Tethered cord rare [HPO:skoehler] 8 / 7739
162
(OMIM) Posterior midline scalp defects 1 / 7739
163
(OMIM) Hemizygous deletion at 4p16.3 1 / 7739
164
(OMIM) Contiguous gene deletion syndrome 23 / 7739
165
(HPO:0011420) Death Occasional [Orphanet] 184 / 7739

Associated genes:

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) Wolf-Hirschhorn syndrome is a congenital malformation syndrome characterized by pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features ('Greek warrior helmet' appearance of the nose, high forehead, prominent glabella, hypertelorism, high-arched eyebrows, protruding eyes, ...
Diagnosis OMIM - Prenatal Diagnosis

Tachdjian et al. (1992) described prenatal diagnosis of 5 cases of WHS studied because of severe intrauterine growth retardation detected on routine ultrasound. At autopsy, the fetuses showed typical craniofacial dysmorphia without microcephaly. ...

Clinical Description OMIM The Wolf-Hirschhorn syndrome is characterized by severe growth retardation and mental defect, microcephaly, 'Greek helmet' facies, and closure defects (cleft lip or palate, coloboma of the eye, and cardiac septal defects) (Hirschhorn et al., 1965; Wolf et al., ...
Molecular genetics OMIM Zollino et al. (2000) reported the findings in 16 WHS patients. In 11 patients, hemizygosity of 4p16.3 was detected by conventional prometaphase chromosome analysis; in 4 patients, it was detected by molecular probes on apparently normal chromosomes. One ...
Population genetics OMIM The frequency of Wolf-Hirschhorn syndrome is estimated at 1/20,000 to 1/50,000 births, with a female predilection of 2:1 (Battaglia et al., 1999; Maas et al., 2008).
Diagnosis GeneReviews The diagnosis of Wolf-Hirschhorn syndrome (WHS) is suggested by the characteristic facial appearance, growth delay, psychomotor retardation, and seizures and is confirmed by detection of a deletion of the Wolf-Hirschhorn critical region (WHCR) (chromosome 4p16.3)....
Clinical Description GeneReviews Although previously thought to be separate disorders, Wolf-Hirschhorn syndrome (WHS) and Pitt-Rogers-Danks syndrome (PRDS) are now recognized as forms of the same syndrome [Battaglia et al 2001]. PRDS was described in 1984 in four individuals (two of whom are sisters) with intrauterine growth retardation, short stature, microcephaly, a characteristic face, intellectual disability, and seizures. Twelve years later, Clemens et al [1996] described a distal 4p microdeletion identical to that seen in individuals with WHS in two previously unreported individuals, as well as in the siblings in the original report. The similarity in the size of the WHS and PRDS critical regions in combination with the phenotypic similarities of these syndromes suggests that PRDS and WHS represent the clinical spectrum associated with a single syndrome. ...
Genotype-Phenotype Correlations GeneReviews In order to explain the wide phenotypic variability of WHS, investigators have searched for correlations between size of the 4p deletion and severity of clinical manifestations....
Differential Diagnosis GeneReviews Proximal 4p deletion. Several individuals with an interstitial deletion of 4p have been described. This deletion usually involves bands 4p12-p16, which are proximal to and exclude the WHS critical region. This disorder is distinct from WHS and is a discrete syndrome [Bailey et al 2010]....
Management GeneReviews To establish the extent of disease in an individual diagnosed with Wolf-Hirschhorn syndrome, the following evaluations are recommended:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....