Manifestations

Major Criteria:

Basal cell carcinoma
The most common type of skin cancer and the most common symptom of BCCNS, basal cell carcinomas (BCCs) often form because of too much exposure to sunlight. Developing most often on the head or neck, these cancerous lesions often show up as shiny, pearly nodules, but red patches, scars, and thickened skin are also common. While they do not often metastasize, BCCs invade the surrounding tissue and can cause serious disfigurement. Patients with BCCNS are likely to develop hundreds of BCCs over the course of their lives, so avoiding sun exposure and wearing sun screen are recommended. Most BCCs are removed surgically, although chemotherapy and photodynamic therapy are sometimes used as well. Radiation therapy is not recommended for patients with BCCNS, because the radiation causes even more BCCs to form.


Jaw cysts (Keratocystic odontogenic tumors or Odontogenic keratocysts)
Cyst-like tumors that form on the jaws—usually toward the back of the mandible (lower jaw) but also on the maxilla (upper jaw). They tend to be benign, but they are aggressive – growing to sizes where they can destroy parts of the jaw and teeth. Early treatment is a must. While pain, swelling, and a bad taste in the mouth often occur, KCOTs can also be found on dental X-rays without other symptoms present.


Palmar and/or plantar pits
Small pits appearing in the skin on the palms of the hand and soles of the feet. Usually only 1-2 millimeters across, the pits become easier to see after soaking the hands in warm water for 10 minutes. Persons who do a lot of manual labor will often have more obvious pits because of dirt or grease getting trapped in them.


Calcification of the dura mater:
The dura mater is a tough covering of tissue around the brain. Some folds of the dura mater, especially the cerebral falx or the sellar diaphragm, are known to calcify (harden) with age, but they may do so earlier in patients with BCCNS. Because there aren’t many symptoms associated with this, it is usually detected by various medical scans.

 

Minor Criteria

Macrocephaly
Macrocephaly refers to a person’s circumference measurements of the head as being larger than normal, once the patient’s height has been adjusted for.


Frontal bossing
Individuals with BCCNS may have a more developed or prominent brow line, making the eyes appear slightly sunken. Eyebrows may also be highly arched, giving the face a “glaring” appearance, or they may meet in the middle (a condition called synophrys).


Cleft lip and palate
The bones and soft tissue in the upper mouth may fail to grow together properly, resulting in a cleft or gap in a child’s upper lip and hard palate (roof of the mouth). These clefts can be large or small, occurring on one or both sides of the face. A hole in the roof of the mouth can connect the mouth to the inside of the nose, leading to leaking and speech problems. There can be feeding problems for a baby with a cleft, because its mouth cannot form proper suction; the ear canals may also be improperly formed, leading to middle-ear infections and possible deafness. Surgery is often needed to correct the cleft.


Hypertelorism
Orbital hypertelorism refers to the eyes being set wider than normal.


Sprengel deformity
A condition where a shoulder blade is smaller than usual and sits higher on the back than the other.


Pectus
If the ribs and sternum (breastbone) do not form properly, pectus generally results. In pectus carinatum, the sternum sticks outward, pulling the ribs with it. In pectus excavatum, the sternum sinks inward, giving the chest a sunken appearance and often leading to problems in the heart, lungs, and back.


Syndactyly
Syndactyly is a condition where the patient’s fingers or toes are fused together. Depending on the case, the patient’s skin may have fused, or the bones themselves may grow together.


Hemivertebrae
One side of a patient’s vertebrae may fail to form correctly, resulting in posture problems such as scoliosis.


Hamartoma
X-rays of various bones may show flame-shaped patches on various bones, especially on those in the hands, arms, feet, and legs. These are hamartomas—disorganized, tumor-like growths made of tissue, nerves, and blood vessels.


Ovarian fibroma
Firm, light-colored tumors may form on a female patient’s ovaries. They often calcify (harden) in patients with BCCNS. While fibromas are often benign, they can grow to become cancerous fibrosarcomas.


Medulloblastoma (Infratentorial primitive neuroectodermal tumor)
A highly malignant brain tumor that originates in the cerebellum or posterior fossa (lower rear part of the brain cavity). It grows rapidly and can spread through the spinal fluid to other locations along the brain and spine. These are pediatric tumors and often show up around age 8 or 9, but patients with BCCNS can develop them as early as age 2 or 3. Telltale symptoms include listlessness, vomiting, morning headache, stumbling, double vision, dizziness, and nystagmus (involuntary eye movement).


Other symptoms of BCCNS
While the previous symptoms are the main criteria used in diagnosing BCCNS, there are a number of other ways the disorder can manifest. Please remember, however, that patients usually won’t develop every symptom.


Most Common Symptoms (50% or greater frequency)
Hyperpneumatization of paranasal sinuses. Possibly because of the various ways that BCCNS affects the growth of the skull, patients may complain of increased sinus pressure around the nose.


Skin tags
Known by a variety of names (acrochordon, fibroepithelial polyp, cutaneous papilloma, fibroma molluscum/pendulum, or soft fibroma), skin tags are small, benign tumors that grow on the skin (usually about the size of a grain of rice). They are harmless and painless, although clothing or jewelry can irritate them. Patients with BCCNS may develop more of these than usual


Spina bifida
A birth defect in which some of the vertebrae covering the spinal cord fail to form and close completely. Patients with BCCNS sometimes have a mild form of spina bifida in their upper back; this may not have many obvious symptoms, but can sometimes result in hydrocephalus (too much fluid in the cavities of the brain).


Less Common Symptoms (50% or less frequency)
Calcification of the skin. Calcium deposits may build up underneath the skin, making it feel hardened or tough.


Cerebral anomalies
Various structures in the brain may form improperly. This sometimes leads to various mental disabilities; other times, deformations may not have visible symptoms, but an MRI can detect them.

  • The ventricles (inner cavities) of the brain may be asymmetrical.
  • Various folds of the dura mater(such as the tentorium cerebelli) may calcify.
  • The corpus callorum (the “bridge” between the hemispheres of the brain) may fail to form.
  • The septum pellucidum (a membrane between the ventricles of the brain) may develop cysts, sometimes manifesting as “sham rage.”
  • The choroid plexus (where cerebrospinal fluid is produced) may develop cysts.

Hypogonadism
Male patients with BCCNS may suffer from decreased production of testosterone. This can result in muscle atrophy, sparse or nonexistent facial and body hair, infertility, night sweats, weight gain, poor sleep, depression, or anxiety.


Hypothyroidism
For various reasons, the thyroid gland (found in the neck) may not produce enough thyroid hormone. This can result in fatigue, poor muscle tone, goiter, brittle hair and nails, low heart rate, constipation, and depression.


Hyperparathyroidism
The parathyroid glands (found in the neck, near the thyroid) may produce too much of its hormone. Because this hormone regulates calcium levels in the body, osteoporosis can result. Other symptoms include fatigue, depression, decreased appetite, nausea, and kidney stones.


 Inguinal hernia
Male patients with BCCNS may suffer from inguinal hernias, where some contents of the abdominal cavity may push through the inguinal canal (the hole in the abdominal wall where the testicles and certain nerves stick out into the scrotum). This is generally corrected surgically.


Kidney anomalies
The kidneys may develop abnormally, grow in strange shapes, or form cysts. Sometimes, one kidney will be missing entirely.


Ocular defects
Various problems can occur in patients’ eyes. The most typical problems include the following…


Cataracts: A clouding in the crystalline lens of the eye, leading to focusing problems, difficulty perceiving light and shadows, and eventual blindness.


Chalazion (meibomian gland lipogranuloma): A cyst in the eyelid, similar to a stye, caused by inflamed glands along the edge of the lid. These cysts are often drained or removed surgically; sometimes the swelling causes blepharitis, chronic irritation of the eye.


Corneal opacity: The cornea is the transparent layer of tissue that protects the lens and helps to focus vision. If the cornea goes opaque, then less light gets through and the eye goes blind.


Strabismus: Poor alignment of the eyes-they don’t line up on the same point in space. This affects binocular vision, leading to problems with depth perception. Sometimes, the brain begins to ignore the input from one eye, leading to amblyopia (lazy eye).


Nystagmus: Involuntary “drifting” of the eye. The eye moves first smoothly in one direction, and then suddenly back in the other. This often impairs normal vision.


Coloboma: A hole in one of the structures of the eye, such as the iris, retina, or optic nerve.


Medullated retinal nerve fibers: Normally, the nerve cells in the optic nerve lose their myelin sheaths as their fibers enter the eye through the retina. In some patients with BCCNS, the fibers instead keep these sheaths, impairing vision.


Glaucoma: A group of diseases that affect the optic nerve (responsible for vision, among other things). Left untreated, glaucoma leads to permanent nerve damage and loss of vision—and often total blindness.


Seizures (Paroxysm)
“Seizure” refers to a variety of symptoms resulting from temporary abnormal activity in the brain. The stereotypical symptoms are sudden convulsions and fainting, but it is common to experience vision changes, tachycardia (increased heart rate), sudden memory loss, a state of fear or confusion, a strange feeling in the pit of the stomach, or the sensation of a strange odor. Often some of the minor symptoms will manifest first as a sort of warning sign; this is referred to as an aura. It is uncertain whether seizures in patients with BCCNS are related to epilepsy.


Sensory impairment
For various reasons, patients with BCCNS may be blind, deaf, or anosmic (unable to smell).


Skeletal anomalies
BCCNS often affects the way patients’ skeletons develop. While some of these anomalies can be harmless, they should still be monitored to make sure they don’t affect other systems of the body. The most typical variations include the following:

  • Bilateral hyperplasia of the coronoid process: The coronoid process is a portion of the mandible (lower jaw) that allows some of the jaw muscles to connect to it. Patients with BCCNS may find that their coronoid process has grown too large to fit properly with the rest of the mouth.
  • Fused vertebrae: bones in the patient’s back fuse together.
  • Kyphosis: an improper curve of the spine, resulting in a slouch or hunched back.
  • Lumbarized sacrum: The segments of a patient’s sacrum (the part of the spine that attaches to the hip bone) might not fuse properly, making it seem like there is an extra lumbar vertebra.
  • Mandibular prognathism: a lower jaw that sticks out slightly, causing a “pouting” appearance and possible underbite.
  • Marfanoid build: a build and skeletal structure similar to patients with Marfan syndrome (above-average height; long, slender limbs; and elongated fingers and toes).
  • Polydactyly: an extra finger or toe, generally forming beside the little finger.
  • Scoliosis: the patient’s spine forms sideways curves. This can often be painful or debilitating.
  • Short metacarpals: blunted or shortened bones in the patient’s hands.
  • Spontaneous fractures: bones breaking or cracking without an apparent cause.

Tumors: Because BCCNS is caused by a mutation in a tumor-suppressing gene, patients with the disorder may develop other kinds of tumors over the course of their lives. If a tumor grows malignant, it may metastasize, spreading cancerous cells to other parts of the body through the bloodstream. Tumors associated with BCCNS include, but are not limited to:

  • Cardiac fibroma: firm, grey-white growths that form in the heart, most often in the wall of the left ventricle. If they stick out too far into the ventricle, they can impede the flow of blood.
  • Colorectal polyps: growths in the lower intestine and colon. Symptoms are uncommon, but include rectal bleeding, bloody stool, abdominal pain, and possible constipation or diarrhea.
  • Fetal rhabdomyoma: tumors developing in the heart or skeletal muscle of an unborn child.
  • Meningioma: Tumors arising in the protective tissue around the brain (known as the meninges). Smaller tumors are sometimes found only at autopsy, but larger tumors can put pressure on various parts of the brain, resulting in partial seizures, muscle weakness, and various sensory problems.
  • Mesenteric cysts: Thin-walled cysts that form in the intestines, containing mostly chyle (a mixture of lymph and fat).
  • Sarcomas: A sarcoma is a cancer of the connective tissue (bone or cartilage). However, sarcomas can also form in soft tissues, such as muscle, fat, nerves, and tendons. Sarcomas can strike people at any age, but they only account for 1% of all cases of cancer.
  • Stomach polyps: growths in the fundus (upper portion) of the stomach. Symptoms are rare, but include upper abdominal pain, nausea, and weight loss.