A familial syndrome of progressive cone dystrophy with total colour blindness, optic disc pallor, thin retinal blood vessels, and retinal dystrophy; without retinal pigment changes. There is degenerative liver disease and endocrinous dysfunction (hypothyroidism), diabetes, recidivating abortions respective infertility, and the head has a peculiar look.. Because of high degree of consanguinity there may be other disturbances. The patients seem to age earlier than normal and die prematurely. Inheritance is autosomal recessive.
- Egill Hansen, Ingegerd Frøyshov Larsen and Kåre Berg:
A familial syndrome of progressive cone dystrophy, degenerative liver disease, endocrine dysfunction and hearing defect. 1. Ophtalmological findings.
Acta Ophthalmologica, Copenhagen, 1976, 54: 129-144.
In this first article, published four years after Larsen and Hansen saw their first patients, seven patients, six women and one man, with progressive cone dystrophy are reported:
"One patient developed amaurosis in one eye and fere amaurosis in the other. The least affected patient (13 years of age) has fairly good central cone vision, but a rod response only outside the central area. Attenuated retinal vessels, disc pallor and general atrophic appearance without pigmentation were typical findings. Six of the patients originated from 2 sibships. Increasing impairment of vision during pregnancy was seen in two patients. Pathological glucose tolerance, diabetes, liver disease, endocrinological disturbances, and hearing defects were recorded. Thus, this cone dystrophy appears to be part of a disease affecting several organs. The familial occurrence suggests that this disorder is inherited."
- Ingegerd Frøyshov Larsen, Egill Hansen and Kåre Berg:
Familial syndrome of progressive cone dystrophy, degenerative liver disease and endocrine dysfunction. II. Clinical and metabolic studies.
Clinical Genetics, Copenhagen, 1978, 13: 176-189.
"Six females from two sibships in a family with a high degree of consanguinity and a male from another family are described: all have a new syndrome of total colour blindness (progressive cone dystrophy), liver degeneration and endocrine dysfunction.
The patients showed endocrine defects at different levels of regulation. None of the patients had children; two were probably infertile and three had had repeated abortions. Two patients had primary hypothyroidism and another two had low normal thyroid function with protracted thyrotropin-releasing hormone (TRH) test response, indicating a hypothalamic disorder. A defect in the ACTH reserve, as tested by Matyrapone®, was found in two patients. Diabetes mellitus of the "maturity-onset type of diabetes of the young" was observed in three patients, and a fourth had a borderline glucose tolerance with further impairment during pregnancy. Hypertension was observed in the diabetic patients. Diabetes was seldom present among the relatives, but hypertension occurred frequently.
Four of the patients had liver degeneration, demonstrated by elevated transaminases and unspecific parenchymal degeneration, fatty infiltration and isolated liver cell necrosis in the biopsy.
All the patients, except the youngest, had progressive hearing loss, classified in four cases as neurogenous and probably cochlear. In the boy, the hearing loss was a neurogenous congenital hypacusis. There were several cases of hearing defects among the relatives, so it is difficult to relate this to the syndrome.
Enlarged sella turcica were found in three, and in one of these an "empty sella" was demonstrated by surgery.
Elevated creatine phosphokinase was also observed. All the different lesions suggest a systemic disorder, possibly a membrane defect."
- Kåre Berg, Ingegerd Frøyshov Larsen and Egill Hansen
Familial syndrome of progressive cone dystrophy, degenerative liver disease and endocrine dysfunction. III. Genetic studies. Clinical Genetics, Copenhagen, 1978, 13: 190-200.
"A syndrome of progressive cone dystrophy, endocrine dysfunction and degenerative liver disease has been observed in seven patients, six of whom belonged to one extensive kindred. Genetic analyses revealed a segregation ratio indicating autosomal recessive inheritance of the syndrome, and the kindred from which six of the seven patients originated was heavily inbred. Thus, the results of the segregation analyses as well as of the inbreeding analyses provide evidence that this previously unrecognised disorder is inherited as an autosomal recessive trait.
Genetic marker analyses were conducted with respect to 22 marker systems, and linkage information was obtained with respect to 15 of them. No strong suggestion of linkage emerged from the analyses, but very close linkage could be excluded for several of the genetic marker systems.
Pedigree analysis was helpful in establishing the spectrum of clinical manifestations belonging to the syndrome proper. The data presently available suggest that elevated levels of creatine phosphokinase, which were found in all patients, may be useful in tracing heterozygotes for this disorder. This possibility will be further examined."
In 1972 Ingegerd Frøyshov Larsen and Egill Hansen at about the same time each had a patient with this syndrome. At the time they were both working at Rikshospitalet (National Hospital), where Larsen's patient was in the neurosurgical department. Larsen was then a university lecturer and an assistant physician in the department of endocrinology.
Larsen, who was looking into the patient's pituitary situation, contacted Hansen because the patient, a woman, had a peculiar loss of field of vision. The patient had had poor eyesight from young age, among other things there was photophobia, and the eyesight had deteriorated rapidly. The patient had empty sella, which is a concavity on the superior surface of the body of sphenoid bone that houses the pituitary gland. The patient was operated.
Almost all patients with this syndrome come from a foresting community in eastern Norway. The exception is a male patient who became practically blind. It is possible that his brother was photophobic and that the condition thus is both sporadic and recessive. His twin brother was normal, but an elder bother who died at the age of six months had symptoms similar to the patient's.
Ingegerd Frøyshov Larsen: I conducted something of a detective work, criss-crossing the entire area to find affected persons. I went back 16 generations, covering a time-span of 40 years. All blood samples were delivered to Kåre Berg and his assistants. At the time we only had markers, today so much could have been done.
Egill Hansen: The affected children look normal at birth, but develop photophobia as children. Some become blind at an early age, some have more luck. One patient had a good central vision, but very narrow, and almost no rest of color perception. Colour vision was lost before they became blind.
Kåre Berg: There is a high frequency of consanguinity in affected families. There were 10 great grandparents where there should have been 16. One of the last patients married a man in the family. She gave birth to a daughter with progressive cone dystrophy.