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PEHO syndrome

General Information (adopted from Orphanet):

Synonyms, Signs:	PROGRESSIVE ENCEPHALOPATHY WITH EDEMA, HYPSARRHYTHMIA, AND OPTIC ATROPHY INFANTILE CEREBELLOOPTIC ATROPHY PEHO-LIKE SYNDROME, INCLUDED Progressive encephalopathy - optic atrophy Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy
Number of Symptoms	73
OrphanetNr:	2836
OMIM Id:	260565
ICD-10:	G31.8
UMLs:	C0796122 C1850055
MeSH:	C536317
MedDRA:
Snomed:	442511009

Prevalence, inheritance and age of onset:

Prevalence:	No data available.
Inheritance:	Autosomal recessive [Orphanet]
Age of onset:	Neonatal Infancy [Orphanet]

Disease classification (adopted from Orphanet):

Parent Diseases:

Autosomal recessive syndromic optic atrophy
-Rare eye disease
-Rare genetic disease
Epileptic syndrome
-Rare genetic disease
-Rare neurologic disease
Genetic neurodegenerative disease
-Rare genetic disease
Rare neurodegenerative disease
-Rare neurologic disease
Syndromic lymphedema
-Rare circulatory system disease
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare skin disease

Symptom Information: Sort by abundance

	Symptom Information	Symptom	Abundance	DB Freq
1	(HPO:0010650)	Hypoplasia of the premaxilla	Very frequent [Orphanet]	39 / 7739
2	(HPO:0000293)	Full cheeks	Very frequent [Orphanet]	85 / 7739
3	(HPO:0010804)	Tented upper lip vermilion		47 / 7739
4	(HPO:0100540)	Palpebral edema	Frequent [Orphanet]	31 / 7739
5	(HPO:0000168)	Abnormality of the gingiva	Frequent [Orphanet]	51 / 7739
6	(HPO:0000341)	Narrow forehead	Very frequent [Orphanet]	96 / 7739
7	(HPO:0000286)	Epicanthus	Very frequent [Orphanet]	371 / 7739
8	(HPO:0002705)	High, narrow palate	Very frequent [Orphanet]	308 / 7739
9	(HPO:0003196)	Short nose	Very frequent [Orphanet]	264 / 7739
10	(HPO:0000194)	Open mouth	Very frequent [Orphanet]	70 / 7739
11	(HPO:0000252)	Microcephaly	Frequent [Orphanet]	832 / 7739
12	(HPO:0000153)	Abnormality of the mouth	Very frequent [Orphanet]	60 / 7739
13	(HPO:0011800)	Midface retrusion	Very frequent [Orphanet]	221 / 7739
14	(HPO:0000463)	Anteverted nares	Frequent [Orphanet]	305 / 7739
15	(HPO:0000278)	Retrognathia		100 / 7739
16	(HPO:0000253)	Progressive microcephaly		37 / 7739
17	(HPO:0007965)	Undetectable visual evoked potentials		3 / 7739
18	(HPO:0000572)	Visual loss	Very frequent [Orphanet]	272 / 7739
19	(HPO:0000648)	Optic atrophy		238 / 7739
20	(HPO:0000496)	Abnormality of eye movement	Very frequent [Orphanet]	79 / 7739
21	(HPO:0000356)	Abnormality of the outer ear	Very frequent [Orphanet]	85 / 7739
22	(HPO:0001347)	Hyperreflexia	Very frequent [Orphanet]	363 / 7739
23	(HPO:0002521)	Hypsarrhythmia		43 / 7739
24	(HPO:0100022)	Abnormality of movement	Very frequent [Orphanet]	129 / 7739
25	(HPO:0002360)	Sleep disturbance	Very frequent [Orphanet]	113 / 7739
26	(HPO:0002187)	Intellectual disability, profound		44 / 7739
27	(HPO:0001327)	Photomyoclonic seizures		125 / 7739
28	(HPO:0001250)	Seizures	Very frequent [Orphanet]	1245 / 7739
29	(HPO:0007281)	Developmental stagnation		6 / 7739
30	(HPO:0003469)	Peripheral dysmyelination		3 / 7739
31	(HPO:0002353)	EEG abnormality	Very frequent [Orphanet]	188 / 7739
32	(HPO:0007105)	Infantile encephalopathy		5 / 7739
33	(HPO:0001387)	Joint stiffness	Frequent [Orphanet]	322 / 7739
34	(HPO:0002803)	Congenital contracture	Occasional [Orphanet]	45 / 7739
35	(HPO:0001182)	Tapered finger	Very frequent [Orphanet]	93 / 7739
36	(HPO:0001155)	Abnormality of the hand		54 / 7739
37	(HPO:0008872)	Feeding difficulties in infancy		153 / 7739
38	(HPO:0011968)	Feeding difficulties		240 / 7739
39	(HPO:0004325)	Decreased body weight	Very frequent [Orphanet]	492 / 7739
40	(HPO:0000969)	Edema		117 / 7739
41	(HPO:0012398)	Peripheral edema		12 / 7739
42	(HPO:0010741)	Edema of the lower limbs	Frequent [Orphanet]	34 / 7739
43	(HPO:0007514)	Edema of the dorsum of hands		7 / 7739
44	(HPO:0002205)	Recurrent respiratory infections	Frequent [Orphanet]	254 / 7739
45	(HPO:0003394)	Muscle cramps	Frequent [Orphanet]	106 / 7739
46	(HPO:0006829)	Severe muscular hypotonia		29 / 7739
47	(HPO:0001252)	Muscular hypotonia	Very frequent [Orphanet]	990 / 7739
48	(OMIM)	Lack of developmental development		2 / 7739
49	(OMIM)	Tapered digits		4 / 7739
50	(HPO:0002119)	Ventriculomegaly	Frequent [Orphanet]	253 / 7739
51	(HPO:0000238)	Hydrocephalus	Frequent [Orphanet]	278 / 7739
52	(HPO:0002529)	Neuronal loss in central nervous system		37 / 7739
53	(OMIM)	Visual fixation absent from birth or lost in first months of life		2 / 7739
54	(HPO:0002363)	Abnormality of brainstem morphology	Frequent [Orphanet]	14 / 7739
55	(OMIM)	MRI shows dysmyelination		2 / 7739
56	(HPO:0400004)	Long ear	Very frequent [Orphanet]	94 / 7739
57	(OMIM)	Brain stem atrophy, progressive		2 / 7739
58	(OMIM)	Relative preservation of Purkinje cells, but they are deformed and disaligned		2 / 7739
59	(HPO:0002334)	Abnormality of the cerebellar vermis	Frequent [Orphanet]	137 / 7739
60	(HPO:0012795)	Abnormality of the optic disc	Very frequent [Orphanet]	187 / 7739
61	(HPO:0000007)	Autosomal recessive inheritance		2538 / 7739
62	(OMIM)	'Pear-shaped' face		2 / 7739
63	(OMIM)	Cerebellar atrophy, progressive		6 / 7739
64	(HPO:0002132)	Porencephaly	Frequent [Orphanet]	18 / 7739
65	(OMIM)	Absent cortical responses of somatosensory evoked potentials		2 / 7739
66	(HPO:0002120)	Cerebral cortical atrophy	Very frequent [Orphanet]	187 / 7739
67	(OMIM)	EEG shows hypsarrhythmia		4 / 7739
68	(HPO:0001272)	Cerebellar atrophy		197 / 7739
69	(OMIM)	Curved upper lip		2 / 7739
70	(HPO:0001522)	Death in infancy	Very frequent [Orphanet]	275 / 7739
71	(OMIM)	Neuropathology shows severe neuronal loss in the inner granular layer of the cerebellum		2 / 7739
72	(HPO:0012758)	Neurodevelopmental delay	Very frequent [Orphanet]	949 / 7739
73	(OMIM)	Optic atrophy by 2 years of age		2 / 7739

Associated genes:

ClinVar (via SNiPA)

Gene symbol	Variation	Clinical significance	Reference

Additional Information:

Clinical Description OMIM

Salonen et al. (1991) identified a new form of infantile progressive encephalopathy in 14 patients, 8 of whom were female, from 11 families. The clinical signs included severe hypotonia, convulsions with hypsarrhythmia, profound mental retardation, hyperreflexia, transient or ... Salonen et al. (1991) identified a new form of infantile progressive encephalopathy in 14 patients, 8 of whom were female, from 11 families. The clinical signs included severe hypotonia, convulsions with hypsarrhythmia, profound mental retardation, hyperreflexia, transient or persistent edema, and optic atrophy. Other features included microcephaly and atrophy of the brain, especially in the cerebellar and brainstem areas. Salonen et al. (1991) pictured edema of the hands and tapering of the fingers resembling somewhat the hands in the Coffin-Lowry syndrome (303600). Facial anomalies included a 'pear-shaped' face, protruding lower parts of the earlobes, short nose, and open mouth with curved upper lip. No metabolic abnormality was found. Haltia and Somer (1993) reported the neuropathologic findings in 8 cases: 3 patients in the original group described by Salonen et al. (1991) and 5 others collected from medical records. Two of the 8 patients were sibs. In addition, 1 patient had 1 sib, and another patient had 2 similarly affected sibs. Macroscopically, cerebral and pronounced cerebellar atrophy was seen, the essential histopathologically lesions being confined to the cerebellar cortex and the optic nerve. There was a severe neuronal loss in the inner granular layer of the cerebellum. The Purkinje cells were relatively preserved in number but were small, deformed, and slightly disaligned. Haltia and Somer (1993) found some similarities to congenital cerebellar granular cell hypoplasia and mental retardation (213200); however, mental retardation was less severe, and no epilepsy or optic atrophy was reported. In a combined neuroradiologic and ophthalmologic study, Somer (1993) found that 10 of 21 possible patients had the true PEHO syndrome according to clinical criteria suggested by the authors. All were abnormal at birth, showing hypotonia, drowsiness, or poor feeding. Head circumference was normal at birth, but usually dropped to 2 SD below average during the first year of life. Visual fixation was either absent from birth or lost during the first months of life. Nine patients had peripheral edema in early childhood. The mean age of onset of infantile spasms was 4.9 months, no motor milestones were ever reached, and patellar reflexes were brisk. Brainstem and somatosensory evoked potentials were abnormal in each case studied, cortical responses of somatosensory evoked potentials could not be elicited, and motor conduction velocities became delayed with age. A total of 19 PEHO patients were found in 14 Finnish families in a pattern consistent with autosomal recessive inheritance. Somer (1993) indicated that cerebellar hypoplasia is a cardinal diagnostic feature of PEHO syndrome and suggested that a PEHO-like syndrome (the same clinical manifestations with only mild supratentorial atrophy) may occur. Fujimoto et al. (1995) reported 2 affected sibs, a male and a female, born to healthy parents of Japanese descent who fulfilled the necessary diagnostic criteria for the PEHO syndrome established by Somer (1993) but who lacked supportive criteria of peripheral edema. In the female, there was mild elevation of the plasma lactate level only during the first year of life without an accompanying elevation of lactate in the cerebrospinal fluid. Chitty et al. (1996) described 2 female sibs and 2 unrelated infants (a boy and a girl) with progressive encephalopathy, seizures, which started between 3 days and 13 months of age, characteristic facies, edema of the hands and feet, tapering fingers, and optic atrophy. All 4 patients died between 10 weeks and 34 months of age. Autopsies were declined. MRI, which was performed in 3 cases, showed delay in myelinization but no cerebellar atrophy. The patients reported by Chitty et al. (1996) fit the criteria of PEHO-like syndrome, but noted that the distinction between PEHO and PEHO-like cases remained unclear. Longman et al. (2003) described 2 sisters with a PEHO-like syndrome. The older sister had early epileptic spasms with hypsarrhythmia, visual inattention with optic atrophy, progressive microcephaly, and absence of development. Cranial MRI revealed periventricular white matter changes. Cerebellar hypoplasia, characteristic of true PEHO syndrome, was absent. The MRI changes were interpreted as periventricular leukomalacia due to prenatal ischemia, and a low recurrence risk was suggested. The younger sister was born similarly affected. Longman et al. (2003) noted that the diagnosis of PEHO syndrome is clinical, but cerebellar hypoplasia on neuroimaging is regarded as an additional necessary criterion. A heterogeneous group of PEHO-like patients, who lacked cerebellar hypoplasia but had varying supratentorial abnormalities, had been reported (Somer, 1993; Chitty et al., 1996). The family reported by Longman et al. (2003) was the second report of sibs with a PEHO-like syndrome, and it supported the existence of a distinct, autosomal recessive condition in which neuroimaging abnormalities may be misinterpreted. Field et al. (2003) noted that few patients fulfilling the diagnostic criteria for PEHO syndrome had been reported outside Finland. Field et al. (2003) reported 5 Australian patients, the first with classic features of PEHO syndrome, and 4 who had a PEHO-like disorder. They suggested that the disorder may be more frequent than would be suggested based on the original diagnostic criteria.

Symptoms & Signs